The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases

Klatzmann, David; Abbas, Abul K.

doi:10.1038/nri3823

Review Article
Published: 17 April 2015

The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases

David Klatzmann^1,2,3 &
Abul K. Abbas⁴

Nature Reviews Immunology volume 15, pages 283–294 (2015)Cite this article

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Key Points

Interleukin-2 (IL-2) was discovered as a cytokine that supports the proliferation and differentiation of effector T cells. IL-2 initially entered clinical development based on this activity, in settings such as cancer and infectious diseases.
When used at high doses in patients with melanoma or renal cell carcinoma, IL-2 induces relatively rare (around 7%) but durable complete responses, at the expense of severe side effects. IL-2 has been approved by the US Food and Drug Administration for these indications.
Surprisingly, knockout of the genes encoding IL-2 or IL-2 receptor in mice led to severe autoimmunity, rather than the predicted immune deficiency. This was later explained by a defect in regulatory T (T_Reg) cells, and the discovery that IL-2 is the key cytokine for T_Reg cell function and survival.
Further studies showed that IL-2 also favours the development of activated CD4⁺ T cells towards the T helper 1 (T_H1), T_H2, T_H9 and peripherally induced T_Reg (pT_Reg) cell lineages, rather than the T_H17 and T follicular helper (T_FH) cell lineages. Thus, IL-2 contributes to tipping the immune balance towards regulation rather than inflammation, notably by favouring the differentiation of pT_Reg cells over T_H17 cells; helps to control autoantibody generation by favouring T follicular regulatory cells over T_FH cells; and helps to control autoreactive CD8⁺ effector T cells.
Proof-of-concept clinical trials have shown that at a low dose, IL-2 is well tolerated, induces T_Reg cells and mediates clinical improvements in autoimmune and inflammatory diseases; these findings have been confirmed in additional trials.
These trials and additional experimental work also showed that IL-2 mediates immunoregulation without immunosuppression. This opens the door for broad investigation of the therapeutic potential of low-dose IL-2 in a large number of autoimmune and inflammatory diseases.

Abstract

Depletion of regulatory T (T_Reg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by T_Reg cells. The data imply that there is a balance between effector T cells and T_Reg cells in health and suggest a therapeutic potential of T_Reg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates T_Reg cell populations and thus can control autoimmune diseases and inflammation.

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Main

To avoid immune responses against self-antigens, most self-reactive T cells are eliminated during selection in the thymus. However, this selection process is 'leaky', and potentially harmful self-specific T cells with possible effector activity are released from the thymus. Self-specific T cells do not usually mediate autoimmune diseases because, in a normal immune system, they are suppressed in the periphery by thymus-derived regulatory T (T_Reg) cells^1,2. This T_Reg cell-mediated control is exemplified by three observations: first, humans and mice with a genetically determined T_Reg cell deficit develop multiple organ-specific autoimmune diseases^3,4; second, a quantitative or qualitative defect in T_Reg cells is present in many mouse and human autoimmune diseases⁵; and third, efficient depletion of T_Reg cells in healthy individuals at any time in life induces a rapid autoimmune and inflammatory response that leads to multi-organ autoimmunity⁶. These observations have led to the concept of a balance between T_Reg cells and effector T cells in health that is dysregulated in autoimmune diseases and inflammatory disorders, which have a T_Reg cell insufficiency.

The discovery of T_Reg cells has opened up a new therapeutic possibility in terms of restoring a healthy balance between T_Reg cells and effector T cells through a qualitative and/or quantitative increase in T_Reg cell function. Owing to a lack of drugs that were capable of enhancing T_Reg cell activity in vivo, initial efforts at therapeutic intervention used adoptively transferred T_Reg cells. Clinical improvements after T_Reg cell transfer have been seen in many animal models of autoimmune diseases and, recently, in humans with type 1 diabetes⁷.

The discovery that interleukin-2 (IL-2) is a key cytokine for T_Reg cell differentiation, survival and function^8,9,10 has led to new opportunities for tipping the balance of T_Reg cells and effector T cells towards T_Reg cells. Proof-of-concept clinical trials have shown that at low doses, IL-2 specifically and safely activates T_Reg cells in humans, and also improves autoimmune and alloimmune inflammatory conditions^11,12. These data inspired a broad investigation of the effects of IL-2 in diseases with an immune component, even beyond the field of autoimmunity.

Here, we review historical and current developments in IL-2 therapy, discussing evidence from mechanistic studies and clinical trials that has led to a shift in our understanding of IL-2 from a cytokine that activates effector T cells against cancer when used at a high dose, to a cytokine that activates T_Reg cells to control autoimmunity and inflammation at a low dose.

IL-2 and homeostasis

IL-2 was the first cytokine to be molecularly cloned, and based on its originally discovered action, it was named 'T cell growth factor' (Box 1). Many studies in the 1970s and 1980s convincingly showed that IL-2 is an autocrine survival and proliferation signal for T cells, and stimulates the differentiation of naive T cells into effector T cells¹³. Thus, IL-2 was established as the essential soluble mediator of T cell-dependent effector immune responses and was thought to be required for the development of all such responses.

The birth of an IL-2 paradox. The aforementioned dogma was not challenged until 1993, when it was discovered that knockout of the gene encoding IL-2 in mice led to severe lymphoproliferation and autoimmunity, rather than the predicted immune deficiency¹⁴. This finding was soon followed by the description of similar phenotypes of mice with a knockout of the gene encoding the β-chain of the IL-2 receptor (IL-2Rβ; hereafter referred to as CD122)¹⁵ or IL-2Rα (hereafter referred to as CD25)¹⁶. The description of CD25 as the canonical phenotypic marker of T_Reg cells¹⁷ suggested that IL-2 signalling defects might affect T_Reg cells and lead to autoimmunity. This was confirmed by showing that T_Reg cells are absent in IL-2-deficient or IL-2R-deficient mice, and that adoptive transfer of these cells from normal mice could prevent autoimmunity in the deficient mice¹⁸. The surprising conclusion of these knockout mouse studies is that the dominant role of IL-2 is the maintenance of T_Reg cells, and not the development of effector and memory T cells, because loss of IL-2 signalling leads to a breakdown of immune tolerance and homeostasis. Thus, an agent that had been used for decades to stimulate effector T cells turned out to be dispensable for these cells, and instead is required for activation of the T_Reg cells that suppress effector T cells.

Pleiotropic effects of IL-2. IL-2 is predominantly produced by activated CD4⁺ T cells and, to a lesser extent, by activated CD8⁺ T cells, activated dendritic cells, natural killer (NK) cells and NKT cells¹⁰. IL-2 production following activation of CD4⁺ T cells is transient; it involves increased transcription and stability of IL2 mRNA, followed by transcriptional silencing and degradation of IL2 mRNA⁸.

Three polypeptide chains — CD25, CD122 and IL-2Rγ (CD132) — together form the high-affinity IL-2R (dissociation constant (K_d) = 10⁻¹¹ M)¹⁰. The IL-2-induced oligomerization of IL-2R initiates signal transduction, which is mediated only by the β-chain and γ-chain, through Janus kinase 1 (JAK1)-mediated and JAK3-mediated activation of signal transducer and activator of transcription 5 (STAT5), as well as the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The CD122–CD132 dimer can also signal in the absence of CD25, but has a lower binding affinity for IL-2 (K_d = 10⁻⁹ M)¹⁰. The high-affinity trimeric IL-2R is constitutively expressed by T_Reg cells, whereas other types of T cell only acquire CD25 upon activation¹⁰.

IL-2 has pleiotropic functions (Fig. 1). It supports the development of T_Reg cells in the thymus, although it may be dispensable for this role¹⁹. It is a key survival factor for T_Reg cells in the periphery, and is required for the functional competence and stability of T_Reg cell populations^20,21. The molecular mechanism of IL-2-induced T_Reg cell stability involves, at least in part, epigenetic changes in the FOXP3 locus (which encodes forkhead box P3)^22,23. One canonical feature of FOXP3⁺ T_Reg cells is their inability to produce IL-2 (Refs 22,23).

**Figure 1: Pleiotropic effects of interleukin-2 in controlling autoimmunity.**

Aside from its role in supporting T_Reg cells, the other main functions of IL-2 are to support the proliferation of CD4⁺ T cells, and to support the terminal differentiation of CD8⁺ T cells. In the absence of IL-2 signalling, CD8⁺ T cells respond to a primary infection but fail to respond to secondary antigen exposure²⁴. Prolonged CD25 expression on CD8⁺ T cells favours terminal effector differentiation in vivo^25,26. However, IL-2 neutralization induces autoimmune diseases such as gastritis, diabetes, thyroiditis and neuropathy, which could be adoptively transferred by CD4⁺ and CD8⁺ T cells²⁷, suggesting that the differentiation of effector T cells can occur even in the absence of IL-2.

IL-2 has been shown to promote the development of naive CD4⁺ T cells into peripherally derived T_Reg cells²⁸, T helper 2 (T_H2) cells²⁹, T_H9 cells³⁰ and, in some studies, T_H1 cells³¹. By contrast, IL-2 suppresses the differentiation of CD4⁺ T cells into T_H17 cells³² and T follicular helper (T_FH) cells³³ by a STAT5-dependent mechanism. Thus, IL-2 may suppress germinal centre formation and create a regulatory environment in germinal centres by altering the balance of T follicular regulatory cells (T_FR cells)^34,35,36 and T_FH cells.

NK cells express high levels of the CD122–CD132 dimeric IL-2R⁸. IL-2 mainly stimulates the proliferation of NK cells, and also increases their cytotoxic activity and cytokine production, although to a lesser extent than does IL-12. Type 2 innate lymphoid cells (ILC2s) express high levels of CD25 (Ref. 37) and therefore proliferate in response to IL-2 through activation of the trimeric IL-2R³⁸. This proliferation is accompanied by the production of IL-5, which can, in turn, expand eosinophil populations³⁹. Following stimulation with IL-2, γδ T cells acquire interferon-γ production and cytolytic activity⁴⁰.

In summary, although many studies show multiple effects of IL-2 on a range of immune cell populations, the most consistent finding of studies in which IL-2 is administered or inhibited is an effect on T_Reg cells, and this is the main focus of the remainder of this Review.

High sensitivity of T_Reg cells to IL-2. One of the most important results that has contributed to our understanding of the biology and therapeutic effects of IL-2 is the demonstration that IL-2-induced signalling and downstream gene activation occur at markedly lower concentrations of IL-2 in T_Reg cells than in effector T cells or NK cells⁴¹ (Fig. 2). T_Reg cells have a 10–20-fold lower activation threshold for IL-2 than effector T cells when measured in terms of the level of phosphorylated STAT5 (pSTAT5). Moreover, downstream of pSTAT5, the activation of numerous genes that are important for cell function requires IL-2 doses that are 100-times lower for T_Reg cells than for effector T cells⁴².

**Figure 2: Effector T cells and regulatory T cells show differential use of signalling pathways and differential sensitivity to interleukin-2.**

Importantly, this greater sensitivity to IL-2 is not solely due to a higher level of expression of CD25 on T_Reg cells compared with effector T cells, as T cell blasts that have even higher levels of CD25 are less sensitive to IL-2-mediated activation than are T_Reg cells⁴². The exquisite sensitivity of T_Reg cells to IL-2 could thus also be due to IL-2R signalling specificity. Whereas the MAPK, PI3K–AKT and STAT5 pathways are all activated in effector T cells in response to antigen, co-stimulation and IL-2, T_Reg cells — in which high PTEN expression levels inhibit the PI3K-dependent signalling pathway^43,44 — may be more dependent on IL-2–STAT5 signalling (Fig. 2).

In vivo experiments in mice confirmed these findings. At doses of IL-2 of approximately 20,000–50,000 IL-2 international units (IU) per day, T_Reg cell populations are expanded compared with those from control mice, and they express higher levels of activation markers and are more suppressive. At these doses of IL-2, neither clonal expansion nor activation of CD4⁺ or CD8⁺ effector T cells or of NK cells can be detected (see below).

Box 1: The discovery of interleukin-2 as a T cell growth factor

In the 1950s and 1960s, immunological studies were mostly focused on humoral immune responses and on antibody function and structure, in part because such studies were facilitated by the availability of assays for measuring antibody responses. T cells were studied in more detail from the 1960s onwards and much effort was put into finding ways to culture them. Molecules capable of activating T cells were sought from the supernatant of cultured T cells; they were first detected in supernatants of mixed lymphocyte cultures^115,116. It was another 10 years before it was shown that media from cultures of mitogen-activated cells could support the growth of T cell clones, indicating the presence of a growth factor in these cultures¹¹⁷. Of note, the authors concluded their report of this discovery by stating that the possibility to grow T cells in vitro “may be relevant to immunotherapy”. This protocol was then used to support the proliferation of T cell clones specific for tumour antigens that retained their functional cytolytic activity¹¹⁸. Lymphocytes were rapidly identified as the source of what was known at the time as T cell growth factor. The interplay between T cell growth factor and another molecule produced by non-T cells that could activate T cells, termed lymphocyte activating factor (LAF), led to the development of the interleukin terminology. LAF became known as interleukin-1 (IL-1) and T cell growth factor became known as IL-2, as a result of the hypothesis — now known to be largely incorrect — that T cell growth factor was produced in response to LAF, which was thus put at the top of the cytokine cascade. IL-2 was the first interleukin to be cloned, in 1983 (Ref. 64). The discovery of IL-2 has been outlined in detail elsewhere¹¹⁹.

IL-2 in pathophysiology

The inflammatory disease that develops in mice lacking IL-2 or functional IL-2R is characterized by colitis and the production of multiple autoantibodies^14,15,16, but the specific effects can vary depending on the mouse strain. On the BALB/c background, the dominant phenotype is autoimmune haemolytic anaemia caused by erythrocyte-specific antibodies, whereas in C57BL/6 mice, the dominant phenotype is colitis. Over time, all Il2-knockout mouse strains produce autoantibodies that are specific for nucleoproteins and other self-antigens. Interestingly, the autoantibodies are produced even in germ-free Il2-knockout mice, whereas the colitis is largely abolished when these knockout mice are made germ free^45,46. These data indicate that the defect in IL-2-dependent FOXP3⁺ T_Reg cells results in immune responses against self-antigens (leading to autoantibody production and 'true' autoimmunity), and perhaps also responses against commensal microorganisms in the gut (which may lead to colitis). In all of these models, the disease can be corrected by providing normal T_Reg cells.

Humans with rare mutations in CD25 also develop autoimmunity⁴⁷. The disease caused by IL-2 or IL-2R deficiency is not as severe as that caused by mutations in FOXP3 in humans with immune dysregulation polyendocrinopathy enteropathy X-linked syndrome³ (IPEX syndrome) or in scurfy mice⁴. This might imply that some T_Reg cells are relatively IL-2 independent^48,49. In line with this, it has been shown that IL-15 can substitute for IL-2 to support and expand T_Reg cell populations⁵⁰.

In many individuals with autoimmune disease, IL-2 production is low compared with healthy individuals, and this could result in the instability and defective function of T_Reg cells. This is the case for autoimmune diseases such as type 1 diabetes⁵¹, rheumatoid arthritis⁵² and systemic lupus erythematosus (SLE)⁵³. However, these findings are not typical of all patients with these diseases, and decreased IL-2 production or IL-2R expression is not considered to be a hallmark of most human autoimmune diseases.

Nonetheless, most autoimmune diseases involve a dysregulated balance between T_Reg cells and effector T cells, and thus, providing more IL-2-dependent signalling may help to correct the disease by increasing T_Reg cell number and function, even in the absence of a pre-existing T_Reg cell defect. This idea is highlighted by the therapeutic efficacy of IL-2 in mouse models in which there is not necessarily a measurable IL-2 or IL-2R defect. IL-2 and IL-2–antibody complex (IL-2c)⁵⁴ have been administered in various experimental autoimmune diseases^{55,56,57,58,59,60} or other inflammatory settings^61,62,63, and in all cases showed some (often remarkable) efficacy.

The ups and downs of IL-2 therapy

Therapeutic use of IL-2 in humans is often adjusted to weight (dose per kg) or body surface area (dose per m²). For ease of comparison of different studies, we have converted all dosing to a fixed dose corresponding to an adult of 70 kg and 1.8 m² in the following discussion⁷⁰.

Initial clinical development: why high doses? The field of IL-2 therapy started with the use of IL-2 purified from cell culture supernatant and gained pace after the cloning of IL-2 in 1983 (Ref. 64). Recombinant IL-2 was initially used at high doses, probably because of its short half-life, which was thought to explain the poor clinical response in the early clinical trials carried out with purified IL-2 (Refs 65,66). The first clinical trial reporting efficacy of IL-2 in human cancer⁶⁷ used escalating doses of up to ~120 million IU (MIU), in three bolus infusions every 8 hours, to ensure that “serum levels were continuously maintained at concentration necessary to stimulate high affinity IL-2 receptors” (Ref. 70). Severe side effects were noted, including a generalized vascular leak syndrome (VLS), and increased serum creatinine and bilirubin levels (indicating kidney and liver damage). The maximum tolerated dose of IL-2 was found to be 42–50 MIU every 8 hours (126–150 MIU per day) and at this dosage, some complete clinical responses were observed in patients with renal cell carcinoma or melanoma⁶⁸. Subsequent attempts to lower the IL-2 dose to reduce side effects resulted in decreased efficacy⁶⁹.

Thus, the paradigm was established that (very) high doses of IL-2 were necessary to achieve a clinical response in patients with cancer, with the drawback of severe side effects.

High-dose IL-2 in cancer: lessons learnt. High doses of IL-2 were subsequently extensively used in patients with cancer. Importantly, they brought the first proof of concept that stimulation of immune responses could be a therapeutic modality in cancer. Large studies showed an ~15% response rate to IL-2 treatment, with 7–9% of patients with melanoma or renal cell carcinoma having complete and often long-lasting responses⁷⁰. These results led to the approval of IL-2 therapy by the US Food and Drug Administration for renal cell carcinoma and metastatic melanoma in 1992 and 1998, respectively.

It is striking that more than 20 years later, the mechanisms of the successful immune responses induced by IL-2 therapy in patients with cancer are still not understood, and it is not clear why only some patients respond to high-dose IL-2. The discovery that IL-2 markedly expands T_Reg cell populations could, in part, explain treatment failures in some patients^71,72,73,74.

The clinical efficacy of high-dose IL-2 in some patients with cancer is with the drawback of a high toxicity of the treatment. One of the main complications is VLS, which has recently been attributed to a direct effect of IL-2 on CD25-expressing endothelial cells⁷⁵, and which leads to multi-organ dysfunction. Initial rates of mortality with high-dose IL-2 therapy were up to 4%, with deaths mostly occurring as a result of severe bacterial infections; these were later prevented by antibiotic therapy. Other common side effects of high-dose IL-2 are malaise, nausea and a flu-like syndrome, which are common manifestations of a cytokine storm, as is seen in settings such as acute infection⁷⁶ and graft-versus-host disease (GVHD)⁷⁷.

In summary, high-dose IL-2 has a poor safety profile but a robust efficacy in only a fraction of patients with a restricted set of cancers. High doses of IL-2 are still used in patients with these cancers, although the severe side effects and the inability to identify potential responders have severely restrained the use of high-dose IL-2 (Ref. 70).

The resurrection of IL-2: proof of concept. IL-2 has been available as an approved drug (Proleukin, Novartis; generic name aldesleukin) since 1992, and was thus available for clinical investigations. The effect of IL-2 on T_Reg cells was known since the mid-1990s, but it was more than 10 years before the first trials investigating the ability of IL-2 to promote T_Reg cell activity in humans with autoimmune and inflammatory diseases were initiated^11,12. The common perception of IL-2 among clinicians was that of a very toxic drug that could be useful only in some late-stage cancers. In addition, IL-2 was considered to be a cytokine that primarily stimulates the effector arm of the immune response, and thus could aggravate autoimmune diseases. In fact, the Proleukin drug brochure specifically warns that “Proleukin has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders” (Ref. 121). Thus, most clinicians were not prepared to reconsider IL-2 as a therapy that could suppress immune responses in autoimmune diseases.

In 2006, researchers were searching for means by which to stimulate T_Reg cells in patients with hepatitis C virus-induced vasculitis (HCV-induced vasculitis). It had previously been shown that patients with HCV-induced vasculitis had a deficiency in the number of T_Reg cells⁷⁸ and that the resolution of the vasculitis after treatment with antivirals or rituximab was associated with a normalization of T_Reg cell numbers^79,80. IL-2 was thus suggested as a potential therapy for HCV-induced vasculitis, on the basis of a major T_Reg cell population expansion that had been observed in patients with cancer who were treated with high-dose IL-2 (Ref. 73). To avoid the severe side effects of high-dose IL-2 and also prevent, as far as possible, the activation of effector T cells, it was thought that using low-dose IL-2 could be the solution. Indeed, low-dose IL-2 had been well tolerated in other indications⁸¹ and the constitutively high levels of expression of CD25 on T_Reg cells could make them more sensitive than effector T cells to IL-2 (although this had not been definitively shown at the time).

Patients with HCV-induced vasculitis were treated with low-dose IL-2, with doses ranging from 1.5 MIU to 3 MIU per day. Patients received a cumulative dose of 50 MIU administered over 2 months¹¹, which corresponds to one-third of the daily dose administered to some patients with cancer. The treatment was well tolerated, and there was a greater than twofold expansion of activated T_Reg cell populations with no detectable activation of effector T cells. A marked anti-inflammatory activity of IL-2 was also observed. Of note, a significant clinical improvement was seen in eight out of ten patients¹¹. IL-2 was also shown to have beneficial effects for the treatment of chronic GVHD, an alloimmune inflammatory disease occurring after allogeneic haematopoietic stem cell transplantation (aHSCT)¹². The results of these two trials showed that low-dose IL-2 could be a novel class of immunoregulatory drug that functions by inducing the expansion and/or activation of T_Reg cells. The door was thus opened for IL-2 therapy to be 'resurrected' into clinical use in the form of low-dose IL-2 to control autoimmunity and inflammation.

Clinical development of low-dose IL-2

The terminology 'low-dose IL-2' requires clarification. Of note, mouse models are not useful for defining low doses of IL-2 as applicable to humans because the IL-2 doses that stimulate T_Reg cells without stimulating effector T cells in mice (~20,000 IU) correspond to very high equivalent doses by weight for humans. In the cancer field, the term low-dose IL-2 has been used for doses of ~5 MIU per injection. However, these were given three times a day for long treatment periods, with the total amount of IL-2 administered to each patient being in excess of 100 MIU. In evaluating the safety and biological effects of low-dose IL-2, it is therefore important to consider both single and cumulative dosage. In the trials of low-dose IL-2 reviewed here, the single dose varies from 0.09 to 5.4 MIU and the cumulative dose ranges from 1.5 to 52.5 MIU, except for a few patients with chronic GVHD who received up to 320 MIU (see Supplementary information S1 (table)).

Safety. The safety of low-dose IL-2 was initially an important concern, but several trials have now established that low doses of IL-2 are well tolerated. Local reactions at injection sites and flu-like syndromes were the most frequent mild to moderate adverse events in patients or healthy volunteers receiving between 0.18 MIU and 3 MIU of IL-2 per day^11,82,83,84 (Box 2; Fig. 3). Of note, in a double-blind, randomized, placebo-controlled trial, the total number of days on which adverse events were reported during the study was higher in the placebo group than in the IL-2-treated groups⁸². Together, these studies show that at doses that stimulate T_Reg cells, IL-2 is well tolerated.

**Figure 3: Effects of interleukin-2 in patients with autoimmune or inflammatory diseases.**

Main biological findings. The trials of low-dose IL-2 that have been reported so far have used different doses and different schedules of administration. However, the main conclusions are that IL-2 induces robust expansion of the T_Reg cell population, and that the maximum magnitude⁸² and duration⁸⁵ of T_Reg cell population expansion are dose dependent. Some effects could be detected at an IL-2 dose as low as 0.18 MIU per day in healthy volunteers⁸⁶. Although there are so far no descriptions of patients who do not respond to low-dose IL-2, one study has shown significant variations in the T_Reg cell response, with some patients who received the lowest dose of IL-2 (0.33 MIU per day) responding better than patients who received the highest dose (3 MIU per day)⁸². Of note, the minimum dose of IL-2 necessary to stimulate T_Reg cells has not yet been established, and may vary according to the patient and the disease.

The T_Reg cell response to IL-2 has mostly been studied in peripheral blood mononuclear cells (PBMCs). In one study, IL-2 induced a marked increase in the number of T_Reg cells that was accompanied by a marked decrease in the number of infiltrating CD8⁺ effector T cells in scalp biopsies of patients with autoimmune alopecia areata (see below); these patients markedly improved during treatment⁸³. Thus, in line with observations made in animal models, the IL-2-dependent increase in the number of T_Reg cells that is mostly documented in peripheral blood is also seen at the site of the autoimmune manifestation.

The expansion of T_Reg cell populations is accompanied by a marked increase in their expression of activation markers, such as CD25, glucocorticoid-induced TNFR-related protein (GITR; also known as TNFRSF18) and cytotoxic T lymphocyte antigen 4 (CTLA4)^85,87. In addition, the suppressive activity of these activated T_Reg cells is greater than that of control T_Reg cells^11,12,88. Thus, we conclude that IL-2 induces the robust proliferation and activation of T_Reg cells, but its dose–response relationship in health and disease seems to be complex and needs to be investigated further to optimize IL-2 use.

A major proliferative response of CD8⁺CD25⁺FOXP3⁺ T cells to IL-2 has also been observed^11,82. This increase in the number of CD8⁺ regulatory T cells is twofold to fivefold greater than the corresponding increase in the number of CD4⁺ T_Reg cells^11,82; similar observations have been made in mice¹²² and macaques⁸⁸. As CD8⁺CD25⁺FOXP3⁺ T cells are highly suppressive in vitro^88,89,90,122, further studies are warranted to evaluate whether they have therapeutic effects in the context of disease.

NK cells also respond to low-dose IL-2, although much less so than T_Reg cells. In patients with chronic GVHD who received continuous treatment with IL-2, the number of blood NK cells doubled over the course of 8 weeks, whereas the number of T_Reg cells increased sixfold to eightfold¹². In patients with type 1 diabetes, there was only a non-significant trend for a moderate increase in the number of NK cells at the highest dose of IL-2 used (3 MIU per day)^82,85. In healthy volunteers, no effect of IL-2 on total NK cell number was reported. The non-cytotoxic CD56^hi NK cells seemed to be most sensitive to IL-2 (Refs 11,86,87). Thus, low-dose IL-2 may in some cases expand NK cell populations, but in a daily and cumulative dose-dependent manner, and mostly for doses of more than 1 MIU per day.

In patients receiving continuous low-dose IL-2, a significant but asymptomatic eosinophilia peaked at 10% of white cells in the blood after 4 weeks of treatment, and subsequently declined¹². In patients with HCV-induced vasculitis, there was a non-significant increase in the mean number of eosinophils after IL-2 treatment, with only some patients having increased values, and often not for all courses of IL-2 (Ref. 39). A modest but significant increase in the number of eosinophils was also seen in healthy volunteers who received IL-2. In summary, IL-2 does expand eosinophil populations, but in a daily and cumulative dose-dependent manner. At doses of less than or equal to 1 MIU per day, the effect seems to be minimal.

An intriguing and significant dose-dependent decrease in the number of CD19⁺ B cells, which also affected marginal zone B cells, has been reported in two trials of low-dose IL-2 (Refs 11,82), with a strong unexpected correlation between an increase in the number of T_Reg cells and a decrease in the number of B cells⁸². This effect could be linked to an inhibition of T_FH cells and/or a stimulation of T_FR cells. The clinical relevance of these findings remains to be clarified, particularly because B cell inhibition could be advantageous in the case of antibody-mediated autoimmune diseases for which B cell-depleting agents can be efficacious. Along these lines, three ongoing trials of low-dose IL-2 in patients with SLE have noted decreased levels of DNA-specific antibodies following IL-2 administration (see Supplementary information S1 (table)).

Immunomonitoring of patients with type 1 diabetes receiving increasing doses of low-dose IL-2 showed the dose-dependent induction of a regulatory milieu, as assessed by T_Reg cell to effector T cell ratios, T_Reg cell activation markers, plasma cytokine and chemokine levels, and transcriptomics⁸⁵. This study also showed that low-dose IL-2 therapy did not induce IL-2-specific antibodies.

Altogether, doses of IL-2 below or equal to 1 MIU per day seem to specifically induce T_Reg cell expansion and activation, and a decrease in the number of B cells, both of which are desirable effects for the treatment of autoimmune diseases. At doses of more than 1 MIU per day, the effects on T_Reg cells are more marked, but some expansion of NK cell and eosinophil populations can be observed, which might be unwanted in some clinical settings.

Efficacy in human autoimmune and inflammatory diseases. Patients with HCV-induced vasculitis have a set of symptoms including fatigue, arthralgia, purpura, kidney involvement and neuropathy. In eight out of ten patients treated with low-dose IL-2, these symptoms progressively disappeared¹¹. In most cases, clinical improvements started to be observed after the second or third course of IL-2 therapy¹¹. In patients with alopecia areata, regrowth of the scalp and/or body hair was noted in all of the five patients treated with IL-2, and four had a regrowth of scalp hair⁸³. Recently, early clinical results of low-dose IL-2 in patients with SLE that have been presented at meetings have reported marked improvement in clinical scores (see Supplementary information S1 (table)). In one patient with refractory SLE, a rapid induction of clinical remission was reported⁹⁰.

In chronic GVHD, of the 23 patients who were evaluated — all of whom were refractory to systemic glucocorticoid therapy — 12 had a partial response to IL-2 and 11 had stable disease after IL-2 therapy¹². In responding patients, extended therapy led to sustained clinical responses and a lowering of the corticosteroid doses administered, which is an indication of treatment efficacy. Low-dose IL-2 was also investigated for the prevention of GVHD in patients receiving aHSCT⁸⁴. The IL-2 treatment not only reduced the frequency and severity of acute GVHD, but was also accompanied by a reduction in the number of infectious episodes, which are a major post-transplantation complication⁸⁴.

Thus, although the dosing and timing of IL-2 administration may not have been optimal in these preliminary studies, they concordantly show some biological and clinical efficacy of low-dose IL-2 that correlates with the expansion and activation of T_Reg cell populations.

Box 2: The main side effects of low-dose interleukin-2

Any evaluation of the safety and clinical tolerance of low-dose interleukin-2 (IL-2) should bear in mind that relatively few patients have been treated for a long period of time, and that studies have mainly been carried out with no placebo control and often in patients receiving additional potentially toxic treatments. The only serious adverse events that have been reported so far for low-dose IL-2 occurred during the treatment of patients with chronic graft-versus-host disease, who received relatively high cumulative doses of IL-2 together with other immunosuppressants and corticosteroids (see Supplementary information S1 (table)). Most reported adverse events of IL-2 treatment are of mild or moderate severity (grade 1 or 2)¹²⁰. The most frequent adverse events reported in all trials of low-dose IL-2 are injection site reactions and constitutional symptoms (such as fatigue, fever, malaise and arthralgia).

In the only double-blind, placebo-controlled study of low-dose IL-2 reported so far (see Supplementary information S1 (table)), 12, 12, 13 and 19 adverse events were reported in patients who received 0, 0.3, 1 and 3 MIU of IL-2 per day, respectively. Injection site reactions occurred in approximately 30% of the IL-2-treated patients, but these were irrespective of the dose and were not seen for all injections in a given patient. This remains unexplained and might be related to the propensity of IL-2 to form aggregates. Constitutional symptoms seemed to be more dose dependent. However, fatigue was observed more frequently in the placebo group. In total, the number of days during which patients declared adverse events was higher for patients receiving placebo than for patients receiving any dose of IL-2.

In another study, IL-2 was well tolerated in 18 children (7–12 years old) with type 1 diabetes who were treated with IL-2 at a dose of 0.25–1 MIU per day for a mean treatment duration of more than 6 months (D.K., unpublished observations).

No significant abnormalities in patient biochemistry have been reported as a consequence of low-dose IL-2 therapy. Eosinophilia seems to be dependent on the IL-2 dose and scheme of administration. It does not occur in all patients and, for those patients with eosinophilia, it does not occur during all courses of treatment.

The promise of low-dose IL-2

By demonstrating the specificity of the effects of low-dose IL-2 on T_Reg cells and by reporting data that indicate a clinical benefit for patients, the preliminary studies discussed above have given optimism for further investigation. This has also been reinforced by mechanistic studies showing that, at least in theory, low-dose IL-2 should have therapeutic effects on both T cell-mediated and antibody-mediated autoimmune diseases.

The issue of dose and schedule. The current assumption is that the therapeutic potential of low-dose IL-2 is in large part linked to the stimulation of T_Reg cells, which are thus a surrogate marker of efficacy. Therefore, the question is how much T_Reg cell stimulation is required, and for how long, to have significant therapeutic effects in diseases that are often chronic in nature? The initial development of IL-2 therapy in patients with cancer was based on the assumption that constant detection of IL-2 in the serum was necessary for efficacy⁷⁰, but it is not known whether constant T_Reg cell stimulation would be required in autoimmune diseases, or for how long.

By modelling the pharmacokinetics of T_Reg cells during and after a 5-day treatment of IL-2, we defined a 5-day induction course of 1 MIU of IL-2 per day as a scheme that will approximately double the percentage of T_Reg cells in PBMCs, to be followed by a fortnightly injection of 1 MIU of IL-2 as a maintenance treatment that should support an increased number of T_Reg cells at 20–60% above baseline values. This treatment modality is used in our current studies, and preliminary results from 36 patients in the TRANSREG clinical trial have confirmed these predictions. Importantly, we found that this treatment course is well tolerated in the long term (more than 6 months) and does not significantly modify the number of effector T cells, NK cells or eosinophils.

Further clinical trials will be required to better decipher the IL-2 dose–response relationship in terms of the specificity of T_Reg cell stimulation and treatment efficacy (Fig. 4). It should also be mentioned that continuous administration of IL-2 achieved by gene transfer is a possible treatment modality; this has been a convenient approach to use in experimental models^91,92,93 but it would be less easy to adjust treatment over time if applied to humans.

**Figure 4: Possible administration schemes for interleukin-2.**

Immunoregulation without immunosuppression. The main complications of immunosuppression are related to infection. As there is normally a balance between T_Reg cells and effector T cells, and because T_Reg cells also control immune responses to infection that are mediated by effector T cells, the question thus arises as to whether protective antimicrobial immunity would be compromised when enhancing T_Reg cell function in a non-antigen-specific manner. Preclinical and clinical data available so far indicate that this is not the case. The administration of an IL-2-expressing adeno-associated virus vector in mice maintained IL-2 production and the associated increase in the number of T_Reg cells for more than a year⁹³. Under such conditions, which permanently increase the proportion of T_Reg cells to 150–200% of baseline values, no effects were observed on mouse lifespan, clinical signs or tissue histology. Furthermore, when challenged with an influenza virus vaccine or a lethal dose of a mouse-adapted influenza virus, mice receiving long-term administration of IL-2 mounted normal protective immune responses⁹³.

In patients with chronic HCV infection, no increase in viral load was observed during IL-2 treatment despite increased T_Reg cell numbers, and there was even a small but significant decrease in the viral load at the end of the follow-up period¹¹. In the GVHD-prevention trial, the recovery of in vitro immune responses against recall antigens was identical in the IL-2-treated and control groups, and, importantly, a marked decrease in the number of infectious episodes was observed in the treated group as compared with controls⁸⁴. Nevertheless, given the effects of IL-2 on T_FH cells and T_FR cells, and the striking decrease in the number of B cells that has been reported in some trials of IL-2 (Refs 11,82), further studies of humoral responses in individuals treated with IL-2 are warranted.

In the trial of low-dose IL-2 therapy for chronic GVHD, three patients had bacterial infections of grade 3 or higher¹², but these findings are difficult to interpret in light of the other immunosuppressive drugs or corticosteroids that these patients received. Of note, in a trial investigating the adoptive transfer of ex vivo-expanded T_Reg cells in children with type 1 diabetes, one patient contracted an influenza virus infection immediately after the T_Reg cell infusion. The infection resolved normally within a few days, indicating that increased T_Reg cell number did not induce systemic immune suppression⁷.

The apparent preservation of a normal immune response to infection during IL-2 therapy is, in fact, not surprising. Inflammation is controlled by T_Reg cells but it also controls T_Reg cells⁹⁴. At high levels of inflammation, T_Reg cells become less efficient⁹⁵. It is thus expected that a moderate increase in the number of T_Reg cells or their functionality should not affect effector immune responses that are triggered by highly inflammatory events, such as infection or vaccination, as the inflammation would be expected to constrain the T_Reg cell response.

IL-2 and inflammation. On the one hand, T_Reg cells tend to lose their functional capacity in highly inflammatory environments⁹⁴. They might even become unstable, losing FOXP3 expression and converting to a phenotype that is more characteristic of effector CD4⁺ T cells (these converted cells have been termed 'ex-T_Reg cells'), although such a process is much debated⁹⁶. Different mechanisms can regulate the susceptibility of T_Reg cells to inflammation-induced FOXP3 destabilization: FOXP3 expression is downregulated by polyubiquitylation⁹⁷ mediated by the E3 ubiquitin ligase STUB1, which is induced by pro-inflammatory cytokines and lipopolysaccharides⁹⁸; PIM1 kinase phosphorylates a serine residue of human FOXP3, thereby impairing its function⁹⁹; and binding of methyl CpG-binding protein 2 (MeCP2) to FOXP3 stabilizes its expression¹⁰⁰.

On the other hand, T_Reg cells suppress inflammation by multiple mechanisms, including reducing co-stimulation to activate effector T cells, consuming IL-2 and secreting immunosuppressive cytokines such as IL-10. The anti-inflammatory effects of T_Reg cells have been observed in various models of inflammatory diseases in mice. In a model of atherosclerosis that spontaneously develops in low-density lipoprotein receptor-knockout mice, T_Reg cell depletion aggravated atherosclerosis and T_Reg cell repletion improved it⁶¹. In line with these observations, treatment with IL-2 also improved atherosclerotic lesions^101,102. Recent reports confirmed that T_Reg cells can improve other inflammatory conditions, such as acute lung injury¹⁰³, muscular dystrophy⁶³ or beryllium-induced granulomatous inflammation⁶². In the muscular dystrophy model, treatment with IL-2c increased the number of T_Reg cells and the IL-10 concentration in muscle, resulting in decreased myofibre injury. In humans treated with IL-2, the analysis of the entire transcriptome of PBMCs suggested a major anti-inflammatory role of low-dose IL-2 (Ref. 11).

These results warrant the investigation of low-dose IL-2 in inflammatory diseases or conditions that are not caused by autoimmune or alloimmune reactions (Fig. 3).

IL-2 in other indications. T_Reg cells have a role in controlling allergy, as indicated by the presence of this symptom in the IPEX syndrome. IL-2c has been shown to improve an experimental form of allergy in mice¹⁰⁴. Thus, IL-2 also has some potential for the treatment of allergy. However, the dose-dependent eosinophilia that can be induced by IL-2 should be carefully considered in terms of the application of this therapy to asthma, in which the harmful role of eosinophils is still debated¹⁰⁵. Furthermore, ILC2s can respond to IL-2 by producing IL-13, which is detrimental in allergy and asthma¹⁰⁶. IL-2 has already been evaluated, with some success, in the fields of HSCT^12,84 and solid organ transplantation¹⁰⁷.

Ageing of the immune system is associated with abnormalities of the T cell repertoire, with the appearance of oligoclonal expansions¹⁰⁸. Injection of T_Reg cells into old mice or the treatment of these mice with IL-2 prevented such oligoclonal T cell expansions¹⁰⁹. The role of IL-2 in preserving T cell homeostasis during ageing should be more thoroughly investigated.

Second-generation IL-2 and combination therapies. Fusions of IL-2 with carrier proteins, such as the Fc domain of IgG, have improved its short half-life¹¹⁰. In addition, several mutant forms of IL-2 have been produced in attempts to alter its ability to bind to different components of the IL-2R, and thus to change its range of activity. One of the earliest such mutant forms of IL-2 was designed to reduce binding to the CD122–CD132 IL-2R dimer (to reduce activation of NK cells and cytokine-mediated toxicity), while preserving its ability to bind to CD25 and hence the trimeric high-affinity IL-2R¹¹¹. This mutant IL-2 protein retained the ability to activate T cells and mediate antitumour effects, but its effect on T_Reg cells has not yet been reported. A different IL-2 mutant has been produced that shows increased binding to CD122 and thus has an increased ability to activate CD8⁺ T cells and NK cells¹¹². Complexes of specific monoclonal antibodies bound to IL-2 have modified the interaction with IL-2R complexes. Depending on the antibody-binding site on IL-2, the IL-2c preferentially activates cells expressing high levels of CD122, such as memory CD8⁺ T cells and NK cells, or CD25-expressing cells such as T_Reg cells^54,113.

Although this field is extremely active and worth pursuing, it should be kept in mind that modified IL-2 or IL-2c with preferential activity for T_Reg cells has not yet been evaluated in patients. It will be many years before an optimized T_Reg cell-focused form of IL-2 is at the same stage of development as 'plain' IL-2, with its 30 years of clinical use. Thus, it is reasonable to propose that clinical development of plain IL-2 should be pursued without waiting for the promises of more effective variants; also, the experience gained with plain IL-2 will help to develop second-generation versions of IL-2.

Combination therapy is often superior to single therapy for complex diseases. High-dose IL-2 is already being tested in combination with checkpoint inhibitors for the immunotherapy of cancer¹¹⁴. Similarly, combinations of low-dose IL-2 with other immune modulators will be worth evaluating in autoimmune diseases. For example, combining low-dose IL-2 with antibodies targeting inflammatory cytokines such as IL-1, IL-6, IL-17 or IL-23 could prove to have synergistic effects in controlling immune-triggered inflammation.

Finally, the possibility to combine the use of IL-2 with antigens to induce specific tolerance is extremely attractive and should be explored.

Conclusions and perspectives

Independent clinical trials have now shown the safety of low-dose IL-2, at least for treatment lengths ranging from several months to a year, which overcomes the most frequent barrier in the development of novel therapies. Moreover, these trials have provided preliminary indications of significant biological and clinical efficacy. Without waiting for a comprehensive understanding of its mechanisms of action, the promises of low-dose IL-2 therapy already warrant broad clinical investigations. These should be aimed at exploring the large field of potential target diseases, but also at transforming current indications of efficacy into proof of efficacy that can only be obtained from state of the art, double-blind, placebo-controlled randomized trials. Comprehensive ancillary studies embedded in these clinical trials should help to harness IL-2 as the next revolution in immunotherapy — immunoregulation without immunosuppression.

References

Sakaguchi, S., Powrie, F. & Ransohoff, R. M. Re-establishing immunological self-tolerance in autoimmune disease. Nature Med. 18, 54–58 (2012).
Article CAS PubMed Google Scholar
Shevach, E. M. & Thornton, A. M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259, 88–102 (2014).
Article CAS PubMed PubMed Central Google Scholar
Moraes-Vasconcelos, D., Costa-Carvalho, B. T., Torgerson, T. R. & Ochs, H. D. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J. Clin. Immunol. 28 (Suppl. 1), 11–19 (2008).
Article CAS Google Scholar
Godfrey, V., Wilkinson, J. & Russell, L. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991).
CAS PubMed PubMed Central Google Scholar
Noack, M. & Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 13, 668–677 (2014).
Article CAS PubMed Google Scholar
Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007). T Reg cell depletion in otherwise healthy individuals triggers brisk autoimmune responses, underscoring the permanent suppression of potentially harmful effector T cells that occurs during homeostasis.
Article CAS Google Scholar
Marek-Trzonkowska, N. et al. Administration of CD4⁺CD25^highCD127⁻ regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care 35, 1817–1820 (2012).
Article PubMed PubMed Central Google Scholar
Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
Article CAS PubMed Google Scholar
Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nature Rev. Immunol. 12, 180–190 (2012).
Article CAS Google Scholar
Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).
Article CAS PubMed PubMed Central Google Scholar
Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011). The first clinical trial showing that low-dose IL-2 is safe and clinically efficacious, and that it induces T Reg cells, in an autoimmune disease.
Article CAS PubMed Google Scholar
Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011). The first clinical trial showing that low-dose IL-2 is safe and clinically efficacious, and that it induces T Reg cells, in an alloimmune inflammatory disease.
Article CAS PubMed PubMed Central Google Scholar
Robb, R. J. Interleukin 2: the molecule and its function. Immunol. Today 5, 203–209 (1984).
Article CAS PubMed Google Scholar
Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993). The first evidence that IL-2 is involved in preventing autoimmune diseases.
Article CAS PubMed Google Scholar
Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).
Article CAS PubMed Google Scholar
Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).
Article CAS PubMed Google Scholar
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995). The discovery of T Reg cells and their role in preventing autoimmune diseases.
CAS PubMed Google Scholar
Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).
Article CAS PubMed Google Scholar
Vang, K. B. et al. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4⁺Foxp3⁺ regulatory T cell development. J. Immunol. 181, 3285–3290 (2008).
Article CAS PubMed Google Scholar
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005).
Article CAS Google Scholar
Barron, L. et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J. Immunol. 185, 6426–6430 (2010).
Article CAS PubMed Google Scholar
Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).
Article CAS PubMed PubMed Central Google Scholar
Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).
Article CAS PubMed Google Scholar
Williams, M. A., Tyznik, A. J. & Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8⁺ memory T cells. Nature 441, 890–893 (2006).
Article CAS PubMed PubMed Central Google Scholar
Kalia, V. et al. Prolonged interleukin-2Rα expression on virus-specific CD8⁺ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91–103 (2010).
Article CAS PubMed Google Scholar
Pipkin, M. E. et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79–90 (2010).
Article CAS PubMed PubMed Central Google Scholar
Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3⁺ CD25⁺ CD4⁺ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).
Article CAS PubMed PubMed Central Google Scholar
Bilate, A. M. & Lafaille, J. J. Induced CD4⁺Foxp3⁺ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).
Article CAS PubMed Google Scholar
Cote-Sierra, J. et al. Interleukin 2 plays a central role in TH2 differentiation. Proc. Natl Acad. Sci. USA 101, 3880–3885 (2004).
Article CAS PubMed PubMed Central Google Scholar
Liao, W. et al. Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl Acad. Sci. USA 111, 3508–3513 (2014).
Article CAS PubMed PubMed Central Google Scholar
Liao, W., Lin, J.-X., Wang, L., Li, P. & Leonard, W. J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nature Immunol. 12, 551–559 (2011).
Article CAS Google Scholar
Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).
Article CAS PubMed Google Scholar
Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012).
Article CAS PubMed PubMed Central Google Scholar
Linterman, M. A. et al. Foxp3⁺ follicular regulatory T cells control the germinal center response. Nature Med. 17, 975–982 (2011).
Article CAS PubMed Google Scholar
Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nature Med. 17, 983–988 (2011).
Article CAS PubMed Google Scholar
Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3⁺ follicular regulatory T cells. J. Immunol. 187, 4553–4560 (2011).
Article CAS PubMed Google Scholar
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Article CAS PubMed PubMed Central Google Scholar
Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunol. 14, 564–573 (2013).
Article CAS Google Scholar
Van Gool, F. et al. Interleukin-5 producing group 2 innate lymphoid cells (ILC2) control eosinophilia induced by interleukin-2 therapy. Blood 124, 3572–3576 (2014).
Article CAS PubMed PubMed Central Google Scholar
Ribot, J. C., Ribeiro, S. T., Correia, D. V., Sousa, A. E. & Silva-Santos, B. Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. J. Immunol. 192, 2237–2243 (2014).
Article CAS PubMed Google Scholar
Yu, A., Zhu, L., Altman, N. H. & Malek, T. R. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30, 204–217 (2009). The molecular explanation for the specific effects of low-dose IL-2 on T Reg cells.
Article CAS PubMed PubMed Central Google Scholar
Yu, A. et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 therapy in type-1 diabetes. Diabetes http://dx.doi.org/10.2337/db14-1322 (2015).
Bensinger, S. J. et al. Distinct IL-2 receptor signaling pattern in CD4⁺CD25⁺ regulatory T cells. J. Immunol. 172, 5287–5296 (2004).
Article CAS PubMed Google Scholar
Walsh, P. T. et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4⁺ CD25⁺ Tregs. J. Clin. Invest. 116, 2521–2531 (2006).
CAS PubMed PubMed Central Google Scholar
Contractor, N. V. et al. Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J. Immunol. 160, 385–394 (1998).
CAS PubMed Google Scholar
Schultz, M. et al. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276, G1461–G1472 (1999).
CAS PubMed Google Scholar
Sharfe, N., Dadi, H. K., Shahar, M. & Roifman, C. M. Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc. Natl Acad. Sci. USA 94, 3168–3171 (1997).
Article CAS PubMed PubMed Central Google Scholar
Smigiel, K. S. et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121–136 (2014).
Article CAS PubMed PubMed Central Google Scholar
Gratz, I. K. et al. Cutting edge: memory regulatory T cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J. Immunol. 190, 4483–4487 (2013).
Article CAS PubMed Google Scholar
Raynor, J. et al. IL-15 fosters age-driven regulatory T cell accrual in the face of declining IL-2 levels. T Cell Biol. 4, 161 (2013).
CAS Google Scholar
Zier, K. S., Leo, M. M., Spielman, R. S. & Baker, L. Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus. Diabetes 33, 552–555 (1984).
Article CAS PubMed Google Scholar
Kitas, G. D., Salmon, M., Farr, M., Gaston, J. S. & Bacon, P. A. Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications. Clin. Exp. Immunol. 73, 242–249 (1988).
CAS PubMed PubMed Central Google Scholar
Lieberman, L. A. & Tsokos, G. C. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J. Biomed. Biotechnol. 2010, 740619 (2010).
Article PubMed PubMed Central CAS Google Scholar
Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody–cytokine immune complexes. Science 311, 1924–1927 (2006). The first report of the properties of IL-2–antibody complexes.
Article CAS PubMed Google Scholar
Rouse, M., Nagarkatti, M. & Nagarkatti, P. S. The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis. Immunobiology 218, 674–682 (2013).
Article CAS PubMed Google Scholar
Hao, J. et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann. Neurol. 69, 721–734 (2011).
Article CAS PubMed PubMed Central Google Scholar
Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).
Article CAS PubMed PubMed Central Google Scholar
Mizui, M. et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4⁻CD8⁻ IL-17-producing T cells. J. Immunol. 193, 2168–2177 (2014).
Article CAS PubMed Google Scholar
Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).
Article CAS PubMed PubMed Central Google Scholar
Liu, R. et al. Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia. Eur. J. Immunol. 40, 1577–1589 (2010).
Article CAS PubMed PubMed Central Google Scholar
Ait-Oufella, H. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nature Med. 12, 178–180 (2006).
Article CAS PubMed Google Scholar
Mack, D. G. et al. Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc. Natl Acad. Sci. USA 111, 8553–8558 (2014).
Article CAS PubMed PubMed Central Google Scholar
Villalta, S. A. et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci. Transl. Med. 6, 258ra142 (2014).
Article PubMed PubMed Central CAS Google Scholar
Taniguchi, T. et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 302, 305–310 (1983).
Article CAS PubMed Google Scholar
Bindon, C. et al. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br. J. Cancer 47, 123–133 (1983).
Article CAS PubMed PubMed Central Google Scholar
Lotze, M. T., Frana, L. W., Sharrow, S. O., Robb, R. J. & Rosenberg, S. A. In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J. Immunol. 134, 157–166 (1985).
CAS PubMed Google Scholar
Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).
Article CAS PubMed Google Scholar
Rosenberg, S. A. et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271, 907–913 (1994). A large study of high-dose IL-2 in patients with cancer.
Article CAS PubMed Google Scholar
Yang, J. C. et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J. Clin. Oncol. 21, 3127–3132 (2003).
Article CAS PubMed Google Scholar
Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).
Article CAS PubMed Google Scholar
Ahmadzadeh, M. & Rosenberg, S. A. IL-2 administration increases CD4⁺ CD25^hi Foxp3⁺ regulatory T cells in cancer patients. Blood 107, 2409–2414 (2006).
Article CAS PubMed PubMed Central Google Scholar
Zhang, H. et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4⁺CD25⁺ regulatory T cells. Nature Med. 11, 1238–1243 (2005).
Article CAS PubMed Google Scholar
Lemoine, F. M. et al. Massive expansion of regulatory T-cells following interleukin 2 treatment during a Phase I–II dendritic cell-based immunotherapy of metastatic renal cancer. Int. J. Oncol. 35, 569–581 (2009).
Article CAS PubMed Google Scholar
Weiss, L. et al. In vivo expansion of naive and activated CD4⁺CD25⁺FOXP3⁺ regulatory T cell populations in interleukin-2-treated HIV patients. Proc. Natl Acad. Sci. USA 107, 10632–10637 (2010).
Article CAS PubMed PubMed Central Google Scholar
Krieg, C., Letourneau, S., Pantaleo, G. & Boyman, O. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc. Natl Acad. Sci. USA 107, 11906–11911 (2010).
Article CAS PubMed PubMed Central Google Scholar
London, N. R. et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl. Med. 2, 23ra19 (2010).
Article PubMed PubMed Central CAS Google Scholar
Ferrara, J. L. Cytokine dysregulation as a mechanism of graft versus host disease. Curr. Opin. Immunol. 5, 794–799 (1993).
Article CAS PubMed Google Scholar
Boyer, O. et al. CD4⁺CD25⁺ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103, 3428–3430 (2004).
Article CAS PubMed Google Scholar
Saadoun, D. et al. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 111, 5334–5341 (2008).
Article CAS PubMed Google Scholar
Landau, D.-A. et al. Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum. 58, 2897–2907 (2008).
Article PubMed Google Scholar
Alric, L. et al. Pilot study of interferon-α-ribavirin-interleukin-2 for treatment of nonresponder patients with severe liver disease infected by hepatitis C virus genotype 1. J. Viral Hepat. 13, 139–144 (2006).
Article CAS PubMed Google Scholar
Hartemann, A. et al. Low-dose interleukin 2 in patients with type 1 diabetes: a Phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 295–305 (2013).
Article CAS PubMed Google Scholar
Castela, E. et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 150, 748–751 (2014).
Article CAS PubMed Google Scholar
Kennedy-Nasser, A. A. et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin. Cancer Res. 20, 2215–2225 (2014).
Article CAS PubMed PubMed Central Google Scholar
Rosenzwajg, M. et al. Low-dose interleukin-2 fosters a dose-dependent regulatory-tuned milieu in T1D patients. J. Autoimmun. 58, 48–58 (2015).
Article CAS PubMed PubMed Central Google Scholar
Ito, S. et al. Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. Mol. Ther. J. Am. Soc. Gene Ther. 22, 1388–1395 (2014).
Article CAS Google Scholar
Matsuoka, K. et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl. Med. 5, 179ra43 (2013).
Article PubMed PubMed Central CAS Google Scholar
Aoyama, A. et al. Low-dose IL-2 for in vivo expansion of CD4⁺ and CD8⁺ regulatory T cells in nonhuman primates. Am. J. Transpl. 12, 2532–2537 (2012).
Article CAS Google Scholar
Chaput, N. et al. Identification of CD8⁺CD25⁺Foxp3⁺ suppressive T cells in colorectal cancer tissue. Gut 58, 520–529 (2009).
Article CAS PubMed Google Scholar
Humrich, J. Y. et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann. Rheum. Dis. 74, 791–792 (2015).
Article PubMed Google Scholar
Gutierrez-Ramos, J. C., Andreu, J. L., Revilla, Y., Vinuela, E. & Martinez, C. Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature 346, 271–274 (1990).
Article CAS PubMed Google Scholar
Goudy, K. S. et al. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J. Immunol. 186, 3779–3786 (2011).
Article CAS PubMed Google Scholar
Churlaud, G. et al. Sustained stimulation and expansion of Tregs by IL-2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin. Immunol. 151, 114–126 (2014).
Article CAS PubMed Google Scholar
Yamaguchi, T., Wing, J. B. & Sakaguchi, S. Two modes of immune suppression by Foxp3⁺ regulatory T cells under inflammatory or non-inflammatory conditions. Semin. Immunol. 23, 424–430 (2011).
Article CAS PubMed Google Scholar
Billiard, F. et al. Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J. Immunol. 177, 2167–2174 (2006).
Article CAS PubMed Google Scholar
Sakaguchi, S., Vignali, D. A. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nature Rev. Immunol. 13, 461–467 (2013).
Article CAS Google Scholar
Van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013).
Article CAS PubMed PubMed Central Google Scholar
Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).
Article CAS PubMed Google Scholar
Li, Z. et al. PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J. Biol. Chem. 289, 26872–26881 (2014).
Article CAS PubMed PubMed Central Google Scholar
Li, C. et al. MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc. Natl Acad. Sci. USA 111, E2807–E2816 (2014).
Article CAS PubMed PubMed Central Google Scholar
Dietrich, T. et al. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis 220, 329–336 (2012).
Article CAS PubMed Google Scholar
Dinh, T. N. et al. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4⁺CD25⁺Foxp3⁺ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation 126, 1256–1266 (2012).
Article CAS PubMed Google Scholar
D'Alessio, F. R. et al. CD4⁺CD25⁺Foxp3⁺ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J. Clin. Invest. 119, 2898–2913 (2009).
Article CAS PubMed PubMed Central Google Scholar
Wilson, M. S. et al. Suppression of murine allergic airway disease by IL-2: anti-IL-2 monoclonal antibody-induced regulatory T cells. J. Immunol. 181, 6942–6954 (2008).
Article CAS PubMed Google Scholar
Rosenberg, H. F., Dyer, K. D. & Foster, P. S. Eosinophils: changing perspectives in health and disease. Nature Rev. Immunol. 13, 9–22 (2013).
Article CAS Google Scholar
Oliphant, C. J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4⁺ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).
Article CAS PubMed PubMed Central Google Scholar
Zheng, X. X. et al. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 19, 503–514 (2003).
Article CAS PubMed Google Scholar
Blackman, M. A. & Woodland, D. L. The narrowing of the CD8 T cell repertoire in old age. Curr. Opin. Immunol. 23, 537–542 (2011).
Article CAS PubMed PubMed Central Google Scholar
Thomas-Vaslin, V. et al. in Immunosuppression — Role in Health and Diseases. (eds Kapur, S. & Portela, M. B.) 125–147 (Intech, 2012).
Google Scholar
Harvill, E. T. & Morrison, S. L. An IgG3-IL2 fusion protein activates complement, binds Fcγ RI, generates LAK activity and shows enhanced binding to the high affinity IL-2R. Immunotechnol. Int. J. Immunol. Eng. 1, 95–105 (1995).
Article CAS Google Scholar
Shanafelt, A. B. et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nature Biotech. 18, 1197–1202 (2000).
Article CAS Google Scholar
Levin, A. M. et al. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 484, 529–533 (2012).
Article CAS PubMed PubMed Central Google Scholar
Rosalia, R. A., Arenas-Ramirez, N., Bouchaud, G., Raeber, M. E. & Boyman, O. Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer. Curr. Opin. Chem. Biol. 23, 39–46 (2014).
Article CAS PubMed Google Scholar
Kaufman, H. L. et al. The society for immunotherapy of cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nature Rev. Clin. Oncol. 10, 588–598 (2013).
Article CAS Google Scholar
Kasakura, S. & Lowenstein, L. A factor stimulating DNA synthesis derived from the medium of leukocyte cultures. Nature 208, 794–795 (1965).
Article CAS PubMed Google Scholar
Gordon, J. & MacLean, L. D. A lymphocyte-stimulating factor produced in vitro. Nature 208, 795–796 (1965).
Article CAS PubMed Google Scholar
Morgan, D. A., Ruscetti, F. W. & Gallo, R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193, 1007–1008 (1976). The first evidence of a T cell growth factor (IL-2) produced by activated T cells.
Article CAS PubMed Google Scholar
Gillis, S., Baker, P. E., Ruscetti, F. W. & Smith, K. A. Long-term culture of human antigen-specific cytotoxic T-cell lines. J. Exp. Med. 148, 1093–1098 (1978).
Article CAS PubMed Google Scholar
Smith, K. A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).
Article CAS PubMed Google Scholar
Edwards, I. R. & Aronson, J. K. Adverse drug reactions: definitions, diagnosis, and management. Lancet 356, 1255–1259 (2000).
Article CAS PubMed Google Scholar
Prometheus Laboratories. Proleukin^® (aldesleukin). [online], (2012).
Churlaud, G. et al. Human and mouse CD8⁺CD25⁺FOXP3⁺ regulatory T cells at steady state and during interleukin-2 therapy. Front. Immunol. http://dx.doi.org/10.3389/fimmu.2015.00171 (2015).

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Acknowledgements

The work of D.K. is funded by French state funds within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02; LabEx Transimmunom); the European Research Council Advanced Grant (ERC-2012-AdG, TRiPoD, Agreement number 322856); the Assistance Publique – Hopitaux de Paris, France; the Sorbonne University, Pierre and Marie Curie Medical School, Paris, France; the Institut National de la Santé et de la Recherche Médicale (INSERM); and Le Centre National de la Recherche Scientifique (CNRS).

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Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, F-75651, France
David Klatzmann
INSERM, UMRS 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, F-75005, France
David Klatzmann
Biotherapy and Département Hospitalo-Universitaire Inflammation-Immunopathology-Biotherapy (i2B), Assistance Publique – Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, F-75651, France
David Klatzmann
Department of Pathology, University of California San Francisco, 94143–0511, California, USA
Abul K. Abbas

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D.K. is an inventor of a patent application claiming low-dose IL-2 for therapy of autoimmune diseases, owned by his academic institution, and licensed to ILTOO Pharma, which he advises and in which he holds shares. A.K.A. declares no competing interests.

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Supplementary information S1 (table)

Main clinical and biological findings from high- to low-dose IL-2 clinical trials (PDF 269 kb)

Glossary

T follicular regulatory cells: (T_FR cells). Cells that are derived from thymus-derived regulatory T cells and share phenotypic characteristics with T follicular helper (T_FH) cells, including the expression of the B cell follicle-homing receptor CXC-chemokine receptor 5. T_FH cells control germinal centre B cells undergoing somatic hypermutation and selection that results in antibody affinity maturation. T_FR cells reduce T_FH cell and germinal centre B cell numbers.
Type 2 innate lymphoid cells: (ILC2s). ILCs are rare cells from the lymphoid lineage — comprising the ILC1, ILC2 and ILC3 subsets — that produce many of the same cytokines as T cells but lack T cell antigen receptors. They have diverse roles in immune responses and inflammation. ILC2s produce type 2 cytokines, such as interleukin-5 (IL-5) and IL-13, and have key roles in anthelminthic responses and allergic lung inflammation.
IL-2 international units: (IL-2 IU). The interleukin-2 (IL-2) IU is a biological activity determined by the ability to support the growth of an IL-2-dependent cell line. In practice, as the manufacture of IL-2 is standardized, 1.1 mg of IL-2 corresponds to 18 million IU.
Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome: (IPEX syndrome). This rare genetic autoimmune disease is caused by mutations in the FOXP3 gene (which encodes forkhead box P3). Affected males present with early-onset severe enteropathy that is usually accompanied by insulin-dependent diabetes (type 1). Other autoimmune manifestations include hypothyroidism, anaemia, thrombocytopenia and neutropenia. Increased serum IgE levels and dermatitis are often also present.
IL-2–antibody complex: (IL-2c). A complex of interleukin-2 (IL-2) and IL-2-specific antibody that has a prolonged half-life compared with IL-2. Its biological activity depends on the antibody. Some complexes preferentially stimulate effector T cells, whereas others preferentially stimulate regulatory T cells.
Vascular leak syndrome: (VLS). VLS (also known as capillary leak syndrome, systemic capillary leak syndrome or Clarkson disease) is characterized by a leakage of fluid from the circulatory system into the interstitial space, resulting in hypotension, haemoconcentration and hypoalbuminaemia.
Cytokine storm: Also known as hypercytokinaemia. The systemic expression of a vigorous immune response resulting in the release of inflammatory mediators into the bloodstream, including cytokines, oxygen free radicals and coagulation factors. The primary symptoms of a cytokine storm are high fever, swelling and redness caused by vascular leak, extreme fatigue and nausea.
Graft-versus-host disease: (GVHD). A common complication of allogeneic stem cell transplantation, in which immune cells from the graft recognize the recipient cells as foreign and attack them. The main target tissues are the liver, skin and gastrointestinal tract. It can be acute (within 100 days of transplantation) and life-threatening, or chronic.
Hepatitis C virus-induced vasculitis: (HCV-induced vasculitis). 10–15% of patients with chronic HCV infection develop systemic cryoglobulinaemic vasculitis. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor and polyclonal IgG that deposit on vascular endothelium, causing vasculitis in organs such as the skin and kidneys, and in peripheral nerves.
Adverse events: Medical occurrences that are temporally (but not necessarily causally) associated with the use of a medicinal product. The severity of adverse events is graded from 1 to 4, with the grades representing mild, moderate, severe and potentially life-threatening events, respectively. Any adverse event that causes death, is life threatening, requires hospitalization, or results in persistent or significant disability or incapacity is considered a serious adverse event.
Alopecia areata: A prevalent autoimmune disease (affecting 1.7% of the general population) that leads to hair loss on the scalp and other areas of the body. Infiltration of CD4⁺ and CD8⁺ T cells around hair follicles is associated with the condition.
TRANSREG clinical trial: An open-label Phase II clinical trial investigating the stimulation of regulatory T cells by low-dose interleukin-2 in 11 autoimmune diseases: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet disease, Wegener granulomatosis, Takayasu disease, Crohn disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis (ClinicalTrials.gov identifier: NCT01988506).

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Klatzmann, D., Abbas, A. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283–294 (2015). https://doi.org/10.1038/nri3823

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Published: 17 April 2015
Issue Date: May 2015
DOI: https://doi.org/10.1038/nri3823

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