Type 1 Diabetes Development Requires Both CD4+ and CD8+ T cells and Can Be Reversed by Non-Depleting Antibodies Targeting Both T Cell Populations

In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

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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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The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

Science Advances ◽

10.1126/sciadv.abc5586 ◽

2020 ◽

Vol 6 (42) ◽

pp. eabc5586 ◽

Cited By ~ 2

Author(s):

Christine Bender ◽

Teresa Rodriguez-Calvo ◽

Natalie Amirian ◽

Ken T. Coppieters ◽

Matthias G. von Herrath

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd8 T Cells ◽

Human Pancreas ◽

Healthy Individuals ◽

High Frequencies ◽

Histocompatibility Complex ◽

Diabetes Development ◽

Specific Trigger

Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8+ T cells from healthy individuals. We quantified PPI-specific CD8+ T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8+ T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8+ T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system.

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One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24

10.2337/figshare.13469904.v1 ◽

2021 ◽

Author(s):

Ada Admin ◽

Teresa Rodriguez-Calvo ◽

Lars Krogvold ◽

Natalie Amirian ◽

Knut Dahl-Jørgensen ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Cd8 T Cells ◽

Pancreatic Tissue ◽

Cell Reactivity ◽

Tissue Samples ◽

Recent Onset ◽

Onset Type

In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

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HLA Class I Epitope Discovery in Type 1 Diabetes: Independent and Reproducible Identification of Proinsulin Epitopes of CD8 T Cells--Report of the IDS T Cell Workshop Committee

Annals of the New York Academy of Sciences ◽

10.1196/annals.1375.003 ◽

2006 ◽

Vol 1079 (1) ◽

pp. 19-23 ◽

Cited By ~ 13

Author(s):

G. G.M PINKSE ◽

C. BOITARD ◽

T. I.M TREE ◽

M. PEAKMAN ◽

B. O ROEP

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Cd8 T Cells ◽

Hla Class I ◽

Class I ◽

Epitope Discovery

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A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance

10.21203/rs.3.rs-257641/v1 ◽

2021 ◽

Author(s):

Mark Anderson ◽

Jeremy Warshauer ◽

Julia Belk ◽

Alice Chan ◽

Jiaxi Wang ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Cd8 T Cells ◽

Autoimmune Diabetes ◽

Single Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

Human Mutation

Abstract Naturally occurring cases of monogenic type 1 diabetes (T1D) provide rare opportunities to establish direct mechanisms that cause this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator signal transducer and activator of transcription 3 (STAT3) was shown to cause neonatal T1D at birth. To investigate the role of STAT3 hyperactivity in T1D, we engineered a novel knock-in (KI) mouse incorporating this highly diabetogenic human mutation (K392R) in the STAT3 gene. These mice developed accelerated diabetes with severe insulitis and insulin autoantibodies, thereby recapitulating the human autoimmune diabetes phenotype. Paired T cell receptor (TCR) and transcriptome (RNA) sequencing in single cells revealed that STAT3-GOF drives the proliferation and clonal expansion of highly cytotoxic effector CD8+ T cells that are resistant to terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and revealed differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed an effector CD8+ T cell reacting against the known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ T cells is sufficient to accelerate diabetes onset. Taken together, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.

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