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An autoimmune stem-like CD8 T cell population drives type 1 diabetes
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An autoimmune stem-like CD8 T cell population drives type 1 diabetes
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Journal Article
An autoimmune stem-like CD8 T cell population drives type 1 diabetes
2022
Overview
CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells
1
. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells. Here we followed the fate of β-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy β-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain β-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.
A population of β-cell-specific autoimmune stem-like CD8 T cells initiates and sustains β-cell destruction and disease in a mouse model of type 1 diabetes.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 45
/ 45/91
/ 64
/ 64/60
/ Animals
/ Antigens
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - metabolism
/ CD8-Positive T-Lymphocytes - pathology
/ CD8-Positive T-Lymphocytes - transplantation
/ Diabetes
/ Diabetes mellitus (insulin dependent)
/ Diabetes Mellitus, Type 1 - immunology
/ Diabetes Mellitus, Type 1 - pathology
/ Disease
/ Female
/ Genes
/ Glucose-6-Phosphatase - immunology
/ Hepatocyte Nuclear Factor 1-alpha - metabolism
/ Humanities and Social Sciences
/ Insulin
/ Insulin-Secreting Cells - immunology
/ Insulin-Secreting Cells - pathology
/ Male
/ Mice
/ Pancreas
/ Receptors, Antigen, T-Cell - metabolism
/ Science
/ Tumors
