Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms

Recognition of beta-cell antigens by autoreactive T cells is a critical step in the initiation of autoimmune Type1 diabetes (T1D). A complete protection from diabetes development in non-obese diabetic (NOD) mice harboring a point mutation in the insulin B-chain 9-23 epitope points to a dominant role of insulin in diabetogenesis. Generation of NOD mice lacking the Chromogranin A protein (<a>NOD.ChgA-/-</a>) completely nullified the autoreactivity of the BDC2.5 T cell and conferred protection from diabetes onset. These results raised the issue concerning the dominant antigen that drives the autoimmune process. Here we revisited the NOD.ChgA-/- mice and found that their lack of diabetes development may not be solely explained by the absence of Chromogranin A reactivity. NOD.ChgA-/- mice displayed reduced presentation of insulin peptides in the islets and periphery, which corresponded to impaired T cell priming. Diabetes development in these mice was restored by antibody treatment targeting regulatory T cells or inhibiting TGFb and PD-1 pathways. Therefore, the global deficiency of chromogranin A impairs recognition of the major diabetogenic antigen insulin, leading to broadly impaired autoimmune responses controlled by multiple regulatory mechanisms.

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IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.702955 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juan Huang ◽

Qiyuan Tan ◽

Ningwen Tai ◽

James Alexander Pearson ◽

Yangyang Li ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Gut Microbiota ◽

Spontaneous Diabetes ◽

Nod Mice ◽

Treg Cells ◽

Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

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Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

10.2337/figshare.13611020 ◽

2021 ◽

Author(s):

Vanessa Mhanna ◽

Gwladys Fourcade ◽

Pierre Barennes ◽

Valentin Quiniou ◽

Hang P. Pham ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cell ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Repertoire Diversity ◽

Pancreatic B Cells ◽

Diabetes Development ◽

Islet Antigen ◽

Cell Clonal Expansion

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

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Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

10.2337/figshare.13611020.v2 ◽

2021 ◽

Author(s):

Vanessa Mhanna ◽

Gwladys Fourcade ◽

Pierre Barennes ◽

Valentin Quiniou ◽

Hang P. Pham ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cell ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Repertoire Diversity ◽

Pancreatic B Cells ◽

Diabetes Development ◽

Islet Antigen ◽

Cell Clonal Expansion

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

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Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

10.2337/figshare.13611020.v1 ◽

2021 ◽

Author(s):

Ada Admin ◽

Vanessa Mhanna ◽

Gwladys Fourcade ◽

Pierre Barennes ◽

Valentin Quiniou ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cell ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Repertoire Diversity ◽

Pancreatic B Cells ◽

Diabetes Development ◽

Islet Antigen ◽

Cell Clonal Expansion

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

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Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice

Journal of Endocrinology ◽

10.1530/joe-14-0396 ◽

2014 ◽

Vol 224 (3) ◽

pp. 235-243 ◽

Cited By ~ 1

Author(s):

Elizabeth S Barrie ◽

Mels Lodder ◽

Paul H Weinreb ◽

Jill Buss ◽

Amer Rajab ◽

...

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Disease Process ◽

Nod Mice ◽

Potential Contribution ◽

Late Time ◽

Early Diabetes ◽

Diabetes Development ◽

Underlying Mechanisms

There is compelling evidence that autoreactive CD8+T cells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an islet-restricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8+T cells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes inItgae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbs to ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE+cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE+CD8+T effectors initiate the disease process.

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Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.

Journal of Experimental Medicine ◽

10.1084/jem.181.3.1145 ◽

1995 ◽

Vol 181 (3) ◽

pp. 1145-1155 ◽

Cited By ~ 414

Author(s):

D J Lenschow ◽

S C Ho ◽

H Sattar ◽

L Rhee ◽

G Gray ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

Autoimmune Diabetes ◽

Disease Process ◽

Nod Mice ◽

Dependent Diabetes Mellitus ◽

Antibody Treatment ◽

Treatment Groups ◽

Nonobese Diabetic ◽

Costimulatory Signals

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.

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Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

Journal of Experimental Medicine ◽

10.1084/jem.20011353 ◽

2002 ◽

Vol 196 (3) ◽

pp. 369-377 ◽

Cited By ~ 190

Author(s):

Marie-Claude Gagnerault ◽

Jian Jian Luan ◽

Chantal Lotton ◽

Françoise Lepault

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Autoimmune Diabetes ◽

Adult Life ◽

Nod Mice ◽

Autoreactive T Cells ◽

Nonobese Diabetic ◽

Autoreactive T Cell ◽

Pancreatic Lymph Nodes ◽

Diabetes Development

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting β cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.

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Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

10.1101/2020.02.06.937839 ◽

2020 ◽

Author(s):

Heejoo Kim ◽

Jelena Perovanovic ◽

Arvind Shakya ◽

Zuolian Shen ◽

Cody N. German ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Target Genes ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Cell Receptor ◽

Glucose Levels ◽

Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

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Faculty Opinions recommendation of Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019222.241532 ◽

2004 ◽

Author(s):

Richard Williams

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Transgenic Mice ◽

T Cell Receptor ◽

Autoimmune Diabetes ◽

Cell Receptor ◽

Unique Role

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