The Long and Winding Road to Understanding and Conquering Type 1 Diabetes

Santamaría, Pere

doi:10.1016/j.immuni.2010.04.003

Cited by 74 publications

(64 citation statements)

References 103 publications

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“…The islet autoreactive CD4 + helper T (T H ) cells and CD8 + cytotoxic T (T C ) cells are involved in the immune pathogenesis of human T1D and NOD mice (19)(20)(21)(22)(23)(24)(25). Recently we showed that IL-7 can promote the development of IFN-γ-producing T H 1 cells, but not IL-17-producing T H 17 cells, from the naïve T cells of humans and of the C57BL/6 mice (26).…”

mentioning

confidence: 99%

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Lee

Logronio

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

112

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Genetic variation in the IL-7 receptor-α ( IL-7R ) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ–producing CD4 + (T H 1) and IFN-γ–producing CD8 + T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.

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mentioning

confidence: 99%

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Lee

Logronio

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

112

View full text Add to dashboard Cite

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“…3B-D, G and 4B-D), consistent with the report of Ekland et al [27], showing that exclusion from FO areas is not a prerequisite for competitive elimination. Nevertheless, the observation led us to speculate that NOD HEL-specific B lymphocytes were better positioned to receive T-cell help; especially in mice on a genetic background where self-tolerance in the T-cell compartment is known to be defective, resulting in the presence of autoreactive T cells capable of providing help [28]. Consistent with this hypothesis, the second difference between self-reactive B lymphocytes on NOD and B6 backgrounds was the enhanced susceptibility of the former to loss of anergy following provision of help (Fig.…”

Section: Discussionmentioning

confidence: 99%

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

et al. 2010

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Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to b-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).Key words: Anergy . B lymphocytes . Self-tolerance . Transgenic mice . Type 1 diabetes Supporting Information available online Introduction B lymphocytes make important contributions to pancreatic b-cell pathogenesis in the NOD mouse model of type 1 diabetes (T1D): first, through secretion of auto-Ab which enhance capture of auto-Ag by DC and NK cells; second, and more importantly, through their action as efficient APC capable of activating and expanding b-cell-reactive CD4 1 T cells [1]. Both pathogenic functions depend on the production of self-reactive Ig by B lymphocytes [2,3], indicating that defective B-lymphocyte self-tolerance is a mechanism that contributes to susceptibility to this disease. Several lines of evidence also point to a pathogenic role for B lymphocytes in human T1D. For example, a recently completed clinical trial has demonstrated that treatment of newly diagnosed T1D patients with the B lymphocyte depleting Ab Rituximab resulted in markedly improved preservation of b-cell function [4]. Furthermore, the fact that the presence and spectrum of b-cell-specific auto-Ab have predictive value in determining T1D susceptibility is consistent with the impairment of B-lymphocyte tolerance in patients developing disease [5]. Studies of models in which BCR Tg specific for natural or neo-self-Ag are expressed in the germ-line of non-autoimmune prone mouse strains have revealed a range of self-tolerance mechanisms in the B-lymphocyte compartment [6]. Which of these mechanisms operate in particular situations is determined by the avidity of the Tg BCR for its cognate self-Ag, i.e. a combination of Ag valency, concentration and receptor affinity [7]. Self-reactive B lymphocytes that encounter cognate Ag with high avidity modify their specificity b...

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“…Type-1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is caused by a chronic, T-cell-dependent autoCorrespondence: Dr. Pere Santamaria e-mail: psantama@ucalgary.ca immune response against insulin-producing pancreatic β cells [1] in which CD8 + cells play a critical role (reviewed in [2]). A relatively large fraction of islet-associated CD8 + cells in NOD mice use highly homologous TCR-α chains and recognize an epitope * These authors contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

IL‐2 promotes the function of memory‐like autoregulatory CD8⁺T cells but suppresses their development via FoxP3⁺Treg cells

et al. 2013

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IL-2 plays a critical role in both effector T-cell development and FoxP3 + CD4 + Treg-cell homeostasis. A reduction in Il2 transcription results in impaired FoxP3 + CD4 + Treg-cell recruitment and function, and accounts for the association between murine Il2 and type 1 diabetes (T1D). The progression of T1D elicits a disease-countering negative feedback regulatory loop that involves the differentiation of low-avidity autoreactive CD8 + T cells into memory-like autoregulatory T cells in a CD4 + Th-dependent manner. Since these autoregulatory T cells express IL-2Rβ (CD122), we hypothesized that their development might also be regulated by IL-2. Here, we investigate the effects of differences in IL-2 expression on this autoregulatory subset. We show that decreased IL-2 production impairs the regulatory capacity of memory-like autoregulatory CD8 + CD122 + T cells. Surprisingly, we also find that a reduction in IL-2 production capacity increases memory autoregulatory CD8 + T-cell formation indirectly, by decreasing the development and function of FoxP3 + Treg cells in nonobese diabetic mice. These results illustrate a complex homeostatic interplay between IL-2, CD4 + Th cells, FoxP3 + CD4 + Treg cells and autoregulatory CD8 + T-cell memory whereby IL-2 controls the function of both Treg-cell subsets, but IL-2-potentiation of FoxP3 + CD4 + Treg-cell function results in the suppression of CD4 + Th-cell activation and autoregulatory memory CD8 + T-cell formation.Keywords: Autoregulatory T-cell memory r CD122 r FoxP3 + CD25 + Treg cells r IL-2 r Type 1 diabetes IntroductionType-1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is caused by a chronic, T-cell-dependent autoCorrespondence: Dr. Pere Santamaria e-mail: psantama@ucalgary.ca immune response against insulin-producing pancreatic β cells [1] in which CD8 + cells play a critical role (reviewed in [2]). A relatively large fraction of islet-associated CD8 + cells in NOD mice use highly homologous TCR-α chains and recognize an epitope * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 394-403 Cellular immune response 395 from islet-specific glucose-6-phosphatase catalytic subunit-related protein or its mimotopes NRP-A7 and NRP-V7) [3,4]. However, this T-cell subset is not homogeneously pathogenic and includes clones engaging peptide-MHC (pMHC) with low avidity, which lack pathogenic activity [5][6][7]. In fact, unlike high-avidity IGRP 206-214 -reactive CD8 + T-cell clones, which differentiate into diabetogenic CTLs, their low-avidity counterparts differentiate into memory-like autoregulatory CD8 + cells with powerful antidiabetogenic properties [8]. We have established that these naive low-avidity CD8 + T-cell clones function as a source of autoantigenspecific negative feedback regulatory loops that aim to counter disease progression by killing and suppressing autoantigen-loaded antigen-presenting cells (APCs) in the pancreas-draining lymph nodes [8]. IL-2...

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The Long and Winding Road to Understanding and Conquering Type 1 Diabetes

Cited by 74 publications

References 103 publications

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

IL‐2 promotes the function of memory‐like autoregulatory CD8⁺T cells but suppresses their development via FoxP3⁺Treg cells

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The Long and Winding Road to Understanding and Conquering Type 1 Diabetes

Cited by 74 publications

References 103 publications

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

IL‐2 promotes the function of memory‐like autoregulatory CD8+T cells but suppresses their development via FoxP3+Treg cells

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IL‐2 promotes the function of memory‐like autoregulatory CD8⁺T cells but suppresses their development via FoxP3⁺Treg cells