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

Gearty, Sofia V, Dündar, Friederike, Zumbo, Paul, Espinosa-Carrasco, Gabriel, Shakiba, Mojdeh, Sanchez-Rivera, Francisco J, Socci, Nicholas D, Trivedi, Prerak, Lowe, Scott W, Lauer, Peter, Mohibullah, Neeman, Viale, Agnes, DiLorenzo, Teresa P, Betel, Doron, Schietinger, Andrea (November 2021) An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature. ISSN 0028-0836

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 programs defining the autoimmune T cell state are unknown. In Type 1 diabetes (T1D), beta cell-specific CD8 T cells destroy insulin-producing beta cells. We followed the fate of beta cell-specific CD8 T cells in non-obese diabetic mice throughout the course of T1D. We identified a stem-like autoimmune progenitor (AP) population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators (AM). pLN AM migrate to the pancreas, where they differentiate further and destroy beta cells. While transplantation of as few as 20 AP induced T1D, as many as 100,000 pancreatic AM failed to do so. Pancreatic AM are short-lived and stem-like AP must continuously seed the pancreas to sustain beta 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 AP to AM. Strategies aimed at targeting the stem-like AP pool could emerge as novel and powerful immunotherapeutic interventions for T1D.

Item Type:	Paper
Subjects:	diseases & disorders > immune system diseases > auto immune diseases bioinformatics diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > immune system diseases organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > nutritional and metabolic diseases > diabetes organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transcriptomes
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	30 November 2021
Date Deposited:	08 Dec 2021 21:48
Last Modified:	23 Jan 2024 21:19
PMCID:	PMC9315050
URI:	https://repository.cshl.edu/id/eprint/40451

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