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

Nature. 2022 Feb;602(7895):156-161. doi: 10.1038/s41586-021-04248-x. Epub 2021 Nov 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Self Renewal
  • Clone Cells / immunology
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology*
  • Disease Models, Animal
  • Female
  • Glucose-6-Phosphatase / immunology
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / pathology
  • Lymph Nodes / immunology
  • Male
  • Mice
  • Receptors, Antigen, T-Cell / metabolism
  • Single-Cell Analysis
  • Stem Cell Transplantation
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Transcriptome


  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Receptors, Antigen, T-Cell
  • Glucose-6-Phosphatase
  • G6pc2 protein, mouse