An autoimmune stem-like CD8 T cell population drives type 1 diabetes.

Publication Type	Academic Article
Authors	Gearty S, Dündar F, Zumbo P, Espinosa-Carrasco G, Shakiba M, Sanchez-Rivera F, Socci N, Trivedi P, Lowe S, Lauer P, Mohibullah N, Viale A, DiLorenzo T, Betel D, Schietinger A
Journal	Nature
Volume	602
Issue	7895
Pagination	156-161
Date Published	11/30/2021
ISSN	1476-4687
Keywords	CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Insulin-Secreting Cells, Stem Cells
Abstract	CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. 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.
DOI	10.1038/s41586-021-04248-x
PubMed ID	34847567
PubMed Central ID	PMC9315050