Interleukin-7 and Type 1 Diabetes

Curr Diab Rep (2014) 14:518 DOI 10.1007/s11892-014-0518-9

PATHOGENESIS OF TYPE 1 DIABETES (A PUGLIESE, SECTION EDITOR)

Interleukin-7 and Type 1 Diabetes Paolo Monti & Ezio Bonifacio

# Springer Science+Business Media New York 2014

Abstract Antigen-experienced T-cells directly target and destroy insulin-producing beta cells in patients with Type 1 diabetes. Consequently, T-cells are also major targets of immunomodulatory strategies that aim to prevent or delay the immune mediated loss of islet beta-cell function. These strategies have had modest success, prompting efforts into better defining the mechanisms that drive the differentiation of quiescent autoreactive clones into pathogenic effector and memory T-cells. Recent and novel findings now indicate that in addition to the classic mechanisms of antigenic recognition, autoreactive T-cell differentiation and expansion can be boosted by the homeostatic cytokine interleukin-7. In this article, we discuss recent evidence of the role of IL-7 mediated T-cell proliferation in the pathogenesis of Type 1 diabetes and the rationale for including immunomodulatory molecules targeting the IL-7/IL-7R axis in immunotherapeutic strategies to control beta-cell autoimmunity. Keywords Type 1 diabetes . Interleukin-7 . IL-7 . IL-7 receptor . Soluble IL-7Rα . sCD127 . Homeostatic proliferation . T-cells

Introduction Type 1 diabetes results from autoimmune destruction of insulin producing beta-cells within the pancreas. The autoimmune This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes P. Monti (*) Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy e-mail: [email protected] E. Bonifacio DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany

process involves both adaptive and innate immune mechanisms but it is widely accepted that T-cells have a predominant role [1]. Autoreactive T-cells specific for beta-cell-associated antigens can be detected in patients and target MHC class I and class II restricted epitopes of the major antigen targets of autoantibodies—proinsulin, glutamic acid decarboxylase 65 (GAD65), islet tyrosine phosphatase 2 (IA-2), and zinc transporter 8—along with other beta-cell proteins such as IGRP and IAPP [2]. Studies of the T-cell responses to beta-cell antigens have provided several key observations. First, unlike autoantibodies that are strongly associated with progression to diabetes and, therefore, excellent markers of preclinical Type 1 diabetes [3], T-cell responses are also commonly found in subjects with no other sign of autoimmunity [4]. Second, autoreactive T-cells found in subjects with Type 1 diabetes or preclinical Type 1 diabetes show characteristics typical of cells that have already encountered their cognate antigen. These characteristics include proliferation to lower antigen concentration or in the absence of co-stimulatory signals [5], reduced telomere length, and the presence of specific late activation and memory markers [6]. Third, autoreactive Tcells in patients with Type 1 diabetes showed an exceptional resistance to inhibition by immuno-modulating molecules [7] and to the tolerogenic network of regulatory T-cells [8]. Controlling the T-cell response to beta cells is difficult as testified by the limited efficacy of recent clinical trials. These include antigen-specific therapy with GAD65 [9], molecule-specific targeting with anti CD3 [10], and CTLA4-Ig [11]. Also more aggressive treatments with profound T-cell depletion were associated with frequent relapse of autoimmunity [12]. The expansion of autoreactive memory T-cells may occur through multiple pathways. Several reports suggest that, in addition to the classical antigen-specific T-cell activation, abnormalities in T-cell homeostasis can trigger homeostatic pathways for T-cell expansion [13]. The interleukin-7 (IL-7) /

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IL-7 receptor (IL-7R) axis is a master regulator of T-cell homeostasis in humans [14, 15]. In this article, we discuss the involvement of the IL-7/IL-7R in the differentiation and expansion of autoreactive clones, how this pathway can be triggered in patients with Type 1 diabetes and whether IL-7 can confer resistance to standard immuno-suppressive and immuno-regulatory approaches. Finally, we discuss whether targeting of the IL-7/IL-7R axis can be a therapeutic option for prevention and treatment of beta-cell autoimmunity.

IL-7 and its Receptor Complex The IL-7R consists of two chains, the IL-7R α-chain (IL-7Rα; also known as CD127) and the common cytokine-receptor γchain (γc; also known as CD132), which in addition to IL-7R, is shared with receptor complexes for IL-2, IL-4, IL-9, IL-15, and IL-21. IL-7 crosslinks the extracellular domains of IL7Rα and γc, and brings together the intracellular domains of the 2 chains. As a consequence, tyrosine kinases Janus kinase 1 (JAK1) and JAK3, which are linked to the γc intracellular domain phosphorylate each other to increase their kinase activity. The intracellular domain of the IL-7Rα is in turn phosphorylated, allowing the signaling molecule signal transducer and activator of transcription 5 (STAT5) to bind the IL7Rα complex. STAT5 is then phosphorylated, allowing its dimerization and subsequent translocation to the nucleus where it promotes gene transcription. The main consequences of the IL-7R signaling cascade are (1) prevention of apoptosis through increasing expression of BCL-2, and (2) cell proliferation [16]. IL-7 is produced by stromal cells in lymphoid tissues and bone marrow and is required for the development of T-cells and for their persistence in the periphery. In the steady state, the immune system relies on low concentrations of IL-7 to regulate T-cell homeostasis and preserve T-cell repertoire diversity. However, during lymphopenia, an IL-7–rich environment provides a milieu for expansion and activation of Tcells. This mechanism of homeostatic expansion was demonstrated to exist in various conditions, such as T-cell responses to tumors [17], graft-vs-host disease [18], HIV infection [19], and autoimmunity [20].

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TCRs with low affinity to cognate self-antigen. Thus, TCR affinity poses a checkpoint for the activation of self-antigenspecific T-cells. Upon activation, antigen-specific T-cell proliferation is primarily driven by autocrine production of IL-2 that in turn engages the IL-2 receptor on the T-cell surface. The alpha chain of the IL-2 receptor (CD25) is upregulated upon antigen recognition, therefore, limiting proliferation of bystander cells (CD25 negative) when IL-2 is secreted. Homeostatic proliferation mediated by IL-7 is able to bypass both the TCR affinity and CD25 expression checkpoints. In contrast to IL-2R, the IL-7R is constitutively expressed on all CD4+ and CD8+ T-cells with higher expression in memory compared with naive subpopulations [21•], and lower expression on regulatory T-cells. When circulating IL-7 is increased, autoreactive clones will receive the same IL-7 stimulation as nonautoreactive clones. Moreover, in the absence of pathogens, MHC molecules present peptides derived from selfproteins. Low affinity interactions with antigen-MHC complexes are required for homeostatic T-cell proliferation during lymphopenia. Thus, IL-7 mediated homeostatic proliferation provides a selective advantage to low affinity autoreactive Tcell clones [22]. Homeostatically expanded T-cells generally keep their preexpansion effector and antigen experience state. However, in some circumstances naïve T-cells may acquire effector functions and develop a memory phenotype after homeostatic expansion [22]. Moreover, recent findings have suggested that progeny of naive T-cells expanded in the presence of IL-7 display stem cell like properties that are not present in T-cells expanded via antigen stimulation. Memory stem T-cells (Tscm) are long-lived memory T-cells with the ability of self-renewal and the plasticity to differentiate into potent effectors. They can be distinguished from other T-cell subsets through their CCR7 + CD62L + CD45RA + CD45R0 − CD27+CD28+CD127+ phenotype. This T-cell subset initially described in mice [23] has been shown in man to play an important role is sustaining long-term chronic T-cell responses in cancer [24] and autoimmunity [25]. Tscm can be generated in vitro by culturing naive T-cells with antigen in the presence of IL-7 and a similar T-cell subset was found in vivo in the human memory compartments even though the involvement of IL-7 in the in vivo generation of Tscm has not been proven [26••].

Homeostatic T-Cell Activation, Proliferation and Differentiation of Autoreactive Clones

IL-7 in Mouse Models of Beta-Cell Autoimmunity

Homeostatic proliferation has been shown to impart selective advantage to autoreactive T-cell clones. The affinity of T-cell receptor (TCR) for cognate antigen-MHC complexes largely determines which clones will be activated and expanded in an immune response. Autoreactive T-cells that escape thymic negative selection processes and enter the periphery express

In the nonobese diabetic (NOD) mouse, a natural condition of lymphopenia was attributed to a reduced number of CD4+ Tcells relative to the nonautoimmune strains such as wild-type BALB/c mice. The condition of CD4+ T-cell insufficiency triggered homeostatic proliferation of residual T-cells, which was regulated by the gamma-chain cytokine IL-21.


Homeostatic proliferation generated pathogenic T-cells and the proliferation rate correlated with insulitis score and diabetes incidence. Injection of Complete Freund’s Adjuvant (CFA) at 3 weeks of age reverted lymphopenia and prevented diabetes in the mice [27]. The rat insulin promoter (RIP)-lymphocytic choriomeningitis virus glycoprotein (GP)-transgenic mouse model revealed a key role of IL-7 in autoimmune diabetes. Adoptive transfer of CD4+ T-cells specific for the I-Ab-restricted LCMV GP61-80 (p13) epitope (Smarta cells) in a polyclonal CD8 TCR repertoire does not lead to a high incidence of diabetes in these mice. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with cyclophosphamide induced lymphopenia was able to profoundly promote the expansion of self-reactive clones and increase the prevalence of diabetes from 20% to 90%. The effect was completely reversible by blocking the IL-7R with a monoclonal antibody [28]. The IL-7/IL-7R axis has been recently implicated in the pathogenesis of beta-cell autoimmunity in the NOD mouse model. Blocking IL-7 receptor-α (IL-7Rα) with monoclonal antibodies in NOD mice prevented autoimmune diabetes after only 2–3 injections starting at week 9 of age and induced durable, complete remission in diabetic mice when injected for 4 weeks at the time of diabetes onset. One report showed that anti-IL-7R treatment blocked diabetogenic effectormemory T-cells (Tem). Diabetogenic Tem cells remained after treatment but had increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-γ production. Tem cells from anti–IL-7Rα–treated mice had lost their pathogenic potential to induce diabetes by adoptive Tcell transfer, indicating that the absence of IL-7 signaling induces cell-intrinsic tolerance [29••]. A second study showed that IL-7Rα antibody therapy reduces IFN-γ–producing CD4+ (TH1) and IFN-γ–producing CD8+ (Tc1) T-cells. IL7R blockade enhanced PD-1 expression in effector T-cells also in this study. Additionally, PD-1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Interestingly, in both models, IL-7R blockade increased the frequency of regulatory T-cells without affecting their suppressor activity [30••].

IL-7 in Human Type 1 Diabetes—Initiation of Autoimmunity Homeostatic T-cell proliferation is strictly associated with lymphopenia in the large majority of clinical conditions. Unlike many other cytokines that act on lymphocytes, IL-7 production is not substantially affected by extrinsic stimuli, and the amount of available IL-7 protein is thought to be regulated by the rate that it is scavenged by T-cells [31]. Increased serum IL-7 concentrations have been observed in

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patients with reduced T-cell numbers during or following viral infections (eg, measles and HIV) and iatrogenic conditions (eg, chemotherapy, radiotherapy, and immunosuppression). Several autoimmune diseases are also associated with reduced white blood cell counts and increased IL-7 [32–34]. With respect to Type 1 diabetes, the relationship between lymphopenia and homeostatic T-cell proliferation appear to be less stringent and other factors are involved. Circulating concentrations of IL-7 are increased in newborns and infants. This overlaps with a period of heightened risk for developing beta-cell autoimmunity. Seroconversion to autoantibody positivity against proinsulin, GAD, IA-2 or ZnT8 is rare prior to 6 months of age but rapidly reaches a peak incidence at 1 year of age in genetically susceptible children [35, 36]. We have postulated that a homeostatic expansion-like environment marked by both increased IL-7 concentrations and increased T-cell responsiveness to IL-7 found in the first year of life may contribute to this heightened risk of seroconversion seen at 1 year of age (37). Proinsulin and GAD65 responsive CD4+ T-cells with a naive phenotype can be detected in neonates with Type 1 diabetes susceptible HLA genotypes already at birth [37•]. Neonates have compromised immune responsiveness in the first months of life, in part explaining why islet autoantibody seroconversion is rare in this period. Competence in mounting responses increases during the first year leading to a period of able responsiveness in a homeostatic expansion rich environment [37•]. In this, case, it is not lymphopenia that drives elevated IL-7 and homeostatic T-cell proliferation, but rather a mechanism to parallel body growth to the expansion of the immune system. Whether dysregulation of IL-7 mediated homeostatic T-cell proliferation is associated with an increased risk of developing autoimmunity is yet to be shown.

IL-7 in Human Type 1 Diabetes—Recurrence of Autoimmunity Patients with long-term Type 1 diabetes who received beta-cell transplants still have autoimmune memory with the capacity to destroy islets. There is good evidence to indicate that islet transplantation can cause relapse of autoimmunity in a small proportion of patients. Occasional patients have dramatic and clinically relevant rises in islet autoantibodies after islet or pancreas transplant without any sign of alloimmunity [38, 39]. Autoreactive T-cell responses can predict islet graft failure [40] and T-cell responses to islet autoantigens are often increased after islet transplantation [41]. The mechanisms of T-cell activation and expansion under immunosuppression likely include support from the homeostatic cytokine IL-7 (Fig. 1). Circulating IL-7 concentration is elevated post islet transplantation, reflecting the homeostatic

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Physiological Regulators of IL-7—Soluble IL-7R (sCD127)

Fig. 1 The IL-7/IL-7R axis in Type 1 diabetes. In normal conditions, physiological amounts of IL-7 are buffered by the soluble form of the IL7Ra (sIL-7Ra). A hyperglycemic environment found in patients with diabetes can disable the IL-7 buffering effect of sIL-7Ra by its glycation, thus, increasing the bio-availability of IL-7. In neonates and during lymphopenia as seen post-transplantation, IL-7 concentration is increased and T-cell responsiveness to IL-7 may also be increased (neonates), so that the availability of circulating IL-7 can bypass the buffering function of the sIL-7Ra, the concentration of which is influenced by polymorphisms of the IL7a gene, and trigger homeostatic proliferation. The engagement of the IL-7R complex promotes cell survival, induces proliferation, and in some conditions also effector function and differentiation of memory stem T-cells. Treatment with anti-IL2-Ra may increase IL-7R complexes on T-cells thereby increasing responsiveness to IL-7. Inhibitors of JAK1 or 3 will inhibit IL-7R signaling. Proliferation can be prevented with MMF, whereas effector function can be prevented by rapamycin

response to the lymphopenic environment associated with immunosuppression [20]. Concomitantly, an increased lymphocyte turnover is observed in T-cells. Homeostatic T-cell proliferation occurs in both CD4+ and CD8+ T-cells, and proliferating cells display CD45RO+ memory phenotype and IFN-gamma production. The antigen specificity of cycling cells is broad and includes the beta-cell antigen GAD65. An IL-7 rich milieu can also modify CD4+CD25+ regulatory T-cell (Treg) homeostasis and function. Treg play a fundamental role in controlling the expansion of autoreactive and alloreactive T-cells. Despite the low expression of the IL-7R, IL-7 induces intracellular signaling in Treg [21•]. While Treg with a memory phenotype remain anergic and do not proliferate in response to IL-7, naive Treg undergo to vigorous expansion and acquire a memory phenotype. Importantly, in the presence of high IL-7 concentration, the capacity of Tregs to suppress proliferation of conventional T-cells in response to TCR activators, including alloantigens and autoantigens, is abrogated. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T-cells, thereby, providing an additional mechanism for activating and expanding alloreactive and autoreactive T-cells.

Both alternative splicing and release of membrane bound CD127 lead to a soluble form of the IL-7R a chain (sCD127) [42]. This is typical of several cytokine receptors. The amount of sCD127 found in the circulation is linked to polymorphisms within the CD127 gene [43]. A single nucleotide polymorphism (SNP) found in exon 6 (rs6897932) is associated with the extent of exon splicing. Transcripts that skip exon 6 (C allele of rs6897932) encode sCD127 [44]. The polymorphism, which leads to increased amounts of sCD127, is weakly associated with susceptibility to Type 1 diabetes, and will lead to slightly higher concentrations of sCD127 in patients with Type 1 diabetes compared with control subjects. Soluble forms of receptors are reported to have antagonistic functions or agonistic functions. For example, an inhibitory action on signaling is reported for tumor necrosis factor (TNF) receptor I and II [45] and the IL-6R subunit gp130 [46]. In contrast, the soluble IL-15 receptor α can increase IL-15mediated proliferation of CD8+ T-cells and natural killer cells up to 50-fold when it is precomplexed to IL-15 [47]. The function of sCD127 is still under debate. Our own study [48••] and a previous report [49] showed that sCD127 can bind to and inhibit the bio-availability of circulating IL-7, thus, representing an important endogenous regulator of the IL-7 biological activity in vivo (Fig. 1). In contrast, a separate report proposes that the sCD127 competes with cellassociated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited [50]. Concentrations of sCD127 are increased at the onset of Type 1 diabetes. We expect this to reflect hyper-reactivity of T-cells in the period prior to diabetes onset. This period is characterized by fluctuating high blood glucose concentrations. Hyperglycemia is a mediator of inflammation [51]. Hyperglycemia can also modify proteins by nonenzymatic glycation as known for hemoglobin, but also for insulin [52]. sCD127 contains many lysine residues as potential sites of glycation, and indeed, we found that sCD127 can be glycated and that glycated forms of sCD127 can be found in the serum of patients at onset of Type 1 diabetes (Fig. 1). Counteracting the increased sCD127 concentrations seen in patients, the glycated form of sCD127 binds poorly to IL-7 and, unlike the nonglycated form of sCD127, is unable to inhibit the biological activity of IL-7 [48••].

Targeting the IL-7/IL-7R Axis Clinical trials using lymphocyte-targeting agents such as antiCD3 (teplizumab or otelixizumab), anti-CD20 (rituximab), or


CTLA4-Ig (abatacept), resulted in transient maintenance of insulin-secretory function in patients with Type 1 diabetes. However, the majority of treated subjects eventually reverted to progressive beta-cell loss, suggesting a recurrence of pathogenic autoreactivity. Therapeutic targeting of proinflammatory cytokines is clinically beneficial in several autoimmune disorders [53, 54].. Strangely, no efforts have been made to target IL-7. As mentioned, antibodies to the IL-7R can block diabetes in the NOD mouse [29••, 30••]. In the absence of a monoclonal antibody or biomolecule for specific IL-7 or IL-7R targeting, we can focus on endogenous regulatory pathways of the IL-7/IL-7R axis. One molecule appears to be sCD127. The affinity of IL-7 for CD127 is not remarkable (Kd=10−8 M) and around 3 logs lower than the affinity of IL-7 to the surface CD127/CD132 complex [55]. Nevertheless, sCD127 concentrations in serum (70–80 ng/mL) are 10,000-fold higher than serum IL-7 concentrations (5 pg/mL) in nonlymphopenic conditions [56]. In view of its relatively low affinity in comparison to the CD127/CD132 complex, even 10-fold increases in IL-7 concentration as seen following islet transplantation [20], is expected to markedly change the free vs bound IL-7 ratio and thereby significantly affect IL-7 bioactivity. The use of modified sCD127 with higher IL-7 binding affinity could have therapeutic benefit. Pharmacologic modulation of the expression of the IL-7R on the T-cell surface may offer the opportunity to tune the Tcell response to IL-7. The IL-7R alpha promoter contains several consensus binding sites for transcription factors that regulate IL-7Rα expression. Both positive and negative regulators occur within T-cells [31]. PU.1 and the GA-binding protein transcription factor (GABP) increase IL-7Rα expression, and growth-factor independent 1 (GFI1) decreases IL7Rα expression. Expression of IL-7Rα is also modified by extracellular factors. Type 1 interferons, glucocorticoids, and tumor-necrosis factor (TNF), can increase IL-7Rα expression [31]. Another biological compound, the soluble HIV Tat protein was shown to down-regulate IL-7R signaling in T-cells [49]. Tat is a 15 kDa viral protein secreted by HIV infected cells, and can be found in the supernatant of in vitro infection cultures as well as in the serum of HIV infected individuals. Interestingly, purified Tat proteins down-regulate IL-7R on Tcells from healthy donors. Soluble Tat proteins are taken up by CD8 T-cells and enter the cytoplasm through a process that requires endosomal acidification. Once in the cytoplasm, Tat translocates to the inner leaflet of the cell membrane, where it interacts with the cytoplasmic tail of CD127, inducing receptor clustering and removal from the cell surface in a microtubule-dependent manner. Finally, Tat appears to direct CD127 to the proteasomes for degradation. Inhibition of down-stream signaling after IL-7R engagement is possible through JAK1 or JAK3 inhibition. Inhibitors

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are already in clinical trial. These include the JAK1 inhibitor GLPC0634 [57], which is in trial for rheumatoid arthritis and Crohn’s Disease, and the JAK3 inhibitor tofacitinib, which is approved for rheumatoid arthritis [58] and in trial for other autoimmune diseases and organ transplantation. Drugs commonly used in transplantation have varying effects on IL-7 promoted homeostatic proliferation. Tacrolimus has no effect on homeostatically expanding T-cells, whereas rapamycin is poorly effective in blocking proliferation but can suppress effector function such as the production of INF-gamma. Mycophenolate mofetil (MMF) reduces the level of proliferation [20]. In contrast, blocking the IL-2Rα promotes IL-7 sensitivity in T-cells in vitro [59].

Conclusions IL-7 mediated homeostatic expansion of autoreactive T-cell clones is an often neglected mechanism that has both pathogenic and therapeutic implications in Type 1 diabetes. Moreover, a number of therapies that are currently tested for Type 1 diabetes immunotherapy may exacerbate IL-7 concentrations. We should, therefore, consider ways in which homeostatic proliferation can be controlled and incorporate such strategies in the combined treatment of Type 1 diabetes.

Compliance with Ethics Guidelines Conflict of Interest Paolo Monti and Ezio Bonifacio declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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