scholarly journals Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms

2019 ◽  
Vol 32 (2) ◽  
pp. 117-131
Author(s):  
Minoru Matsumoto ◽  
Koichi Tsuneyama ◽  
Junko Morimoto ◽  
Kazuyoshi Hosomichi ◽  
Mitsuru Matsumoto ◽  
...  
Keyword(s):  
T Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Peripheral Tolerance ◽  
Type I ◽  
Tolerance Mechanisms ◽  
Thymic Function ◽  
Tissue Specific ◽  
Thymic Stroma ◽  
Antigen Presenting

Abstract Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.

scholarly journals T Helper 2 (Th2) T Cells Induce Acute Pancreatitis and Diabetes in Immune-compromised Nonobese Diabetic (NOD) Mice

1997 ◽  
Vol 186 (2) ◽  
pp. 299-306 ◽  
Author(s):  
Syamasundar V. Pakala ◽  
Michael O. Kurrer ◽  
Jonathan D. Katz
Keyword(s):  
T Cells ◽  
Islet Cell ◽  
Autoimmune Diabetes ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Type I ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Nonobese Diabetic

Autoimmune diabetes is caused by the CD4+, T helper 1 (Th1) cell-mediated apoptosis of insulin-producing β cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

scholarly journals Type I Diabetes-Associated Tolerogenic Properties of Interleukin-2

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Aziz Alami Chentoufi ◽  
Simon Gaudreau ◽  
Alex Nguyen ◽  
Mahmoud Sabha ◽  
Abdelaziz Amrani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Type I Diabetes ◽  
Gene Knockout ◽  
Critical Role ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Peripheral Tolerance ◽  
Type I ◽  
Tolerance Gene

Type 1 Diabetes (T1D) results from insulin-producing beta cells destruction by diabetogenic T lymphocytes in humans and nonobese diabetic (NOD) mice. The breakdown of tolerance has been associated with a defect in the number and the function of naturally occurring regulatory T cells (nTreg) that are the master player in peripheral tolerance. Gene knockout experiments in mouse models have shown a nonredundant activity of IL-2 related to its critical role in inducing nTreg and controlling peripheral T cell tolerance. Whereas strong evidence has suggested that IL-2 is critically required for nTreg-mediated T1D control, several fundamental questions remain to be addressed. In this paper, we highlight the recent findings and controversies regarding the tolerogenic properties of IL-2 mediated through nTreg. We further discuss a potential link between the immunomodulatory role of interleukin-2 and the pathogenesis of type 1 diabetes.

scholarly journals Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

2013 ◽  
Vol 43 (5) ◽  
pp. 1356-1362 ◽  
Author(s):  
Julie Tellier ◽  
Andry Andrianjaka ◽  
Rita Vicente ◽  
Nicolas Thiault ◽  
Geneviève Enault ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Type I ◽  
Diabetes Susceptibility ◽  
Thymic Development

scholarly journals Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes.

1991 ◽  
Vol 174 (3) ◽  
pp. 633-638 ◽  
Author(s):  
J A Shizuru ◽  
C Taylor-Edwards ◽  
A Livingstone ◽  
C G Fathman
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Autoimmune Diabetes ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Type I ◽  
Genetic Dissection ◽  
Beta Gene

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.

scholarly journals T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mai T. Tran ◽  
Pouya Faridi ◽  
Jia Jia Lim ◽  
Yi Tian Ting ◽  
Goodluck Onwukwe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Type I Diabetes ◽  
Binding Motif ◽  
Type I ◽  
Cell Repertoire ◽  
Islet Amyloid ◽  
Autoreactive T Cell ◽  
Β Chain

AbstractHLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.

scholarly journals Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

2011 ◽  
Vol 208 (8) ◽  
pp. 1683-1694 ◽  
Author(s):  
Joyce Wei ◽  
P’ng Loke ◽  
Xingxing Zang ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Peripheral Tolerance ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Specific Expression ◽  
Tissue Specific ◽  
Disease Induction ◽  
Deficient Mice ◽  
Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage

1996 ◽  
Vol 148 (1) ◽  
pp. 139-148 ◽  
Author(s):  
A Amrani ◽  
M Jafarian-Tehrani ◽  
P Mormède ◽  
S Durant ◽  
J-M Pleau ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type I Diabetes ◽  
Interleukin 1 ◽  
Nod Mice ◽  
Experimental Models ◽  
Nod Mouse ◽  
Hypoglycemic Effect ◽  
Type I ◽  
Insulin Effect ◽  
Corticosterone Secretion

Abstract Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1α (mrIL-1α) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1α (12·5 and 50 μg/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1α lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1α had no influence on insulin levels in females, but significantly increased them in males (P<0·0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1α on insulin secretion. Corticosterone secretion was stimulated by mrIL-1α in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1α in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1α is administered to adrenalectomized animals or when mrIL-1α is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1α, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2·5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance. Journal of Endocrinology (1996) 148, 139–148

scholarly journals Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

2008 ◽  
Vol 205 (1) ◽  
pp. 207-218 ◽  
Author(s):  
Renu Jain ◽  
Danielle M. Tartar ◽  
Randal K. Gregg ◽  
Rohit D. Divekar ◽  
J. Jeremiah Bell ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Acid Decarboxylase ◽  
Type I ◽  
Pancreatic Cell ◽  
Disease Stages ◽  
Free Antigen

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

Sign in / Sign up

Export Citation Format

Share Document