Interleukin-21 Receptor-Mediated Signals Control Autoreactive T Cell Infiltration in Pancreatic Islets

Belle, Tom L. Van; Nierkens, Stefan; Arens, Ramon; Herrath, Matthias G. von

doi:10.1016/j.immuni.2012.04.005

Cited by 64 publications

(64 citation statements)

References 37 publications

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“…While, at first sight, these findings are hard to reconcile, it is probably reasonable to conclude that IL-21 can act on both CD4 and CD8 T cells to promote diabetes, with the relative importance of each axis being dependent upon the precise experimental context. The effects of IL-21 on the CD4 compartment include the promotion of cell survival, as illustrated by the increased sensitivity of IL-21R -/-T cells to activationinduced cell death [85]. In addition, IL-21 may act on macrophages, increasing their capacity to stimulate CD4 T cell proliferation [86].…”

Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

“…In a virus-induced diabetes model, pancreatic DCs required IL-21R signals to acquire CCR7 and MHC class II and migrate to the draining lymph node [85]. Indeed, disease resistance associated with IL-21R deficiency could be overcome by the adoptive transfer of IL-21R-sufficient DC [85]. This contrasts with the capacity of IL-21 to inhibit DC maturation in vitro [102], and suggests that its effects may be highly context-dependent.…”

Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

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CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

153

113

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SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

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Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

153

113

View full text Add to dashboard Cite

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“…The contribution of IL-21 to a number of autoimmune diseases, including systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, experimental allergic autoimmune encephalomyelitis, psoriasis, diabetes mellitus, and inflammatory bowel disease, was reported (13)(14)(15)(16)(17)(18)(19). Elevated IL-21 levels were found in lupus-prone BXSB.Yaa mice, and autoimmune features were attenuated in BXSB.Yaa and MRL-Fas lpr mice following genetic deletion of IL-21R or IL-21 blockade (20)(21)(22)(23).…”

Section: Nterleukin-21 Is a Member Of The Type I Cytokine Family Wimentioning

confidence: 99%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell–mediated response, respectively. Induction of acute GVHD using IL-21R–deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell–driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

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“…DCs loaded with beta-cell-derived proteins can be visualized within the PLNs [26]. Two subsets of DCs have been described within islets, the CD11b subset, expresses CCR7, a chemokine receptor associated with DC migration into draining lymph nodes [27,28]. CD103 + DCs were numerically deficient in the PLNs of CCR7 knockout mice, suggesting that CD103 + DC represents the major migratory population derived from islets (Figure 1) [28].…”

Section: Autoreactive T Cells Are Primed In the Pancreatic Lymph Nodesmentioning

confidence: 99%

“…This facilitates the migration of antigen-loaded DCs from islets into the PLN, where they can cross-present antigens to autoreactive CD8 + T cells [27]. Thus, the imbalance between IL-2 and IL-21 within the islet environment results in declining Treg function, with a concomitant increase in effector T cell function (Figure 3).…”

Section: Immune Regulatory Mechanisms Within Islets Fail To Control Pmentioning

confidence: 99%

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

et al. 2012

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Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4 + T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8 + T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.

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Interleukin-21 Receptor-Mediated Signals Control Autoreactive T Cell Infiltration in Pancreatic Islets

Cited by 64 publications

References 37 publications

CD4 T cell differentiation in type 1 diabetes

CD4 T cell differentiation in type 1 diabetes

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

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