TY - JOUR
T1 - An autoimmune stem-like CD8 T cell population drives type 1 diabetes
AU - Gearty, Sofia V.
AU - Dündar, Friederike
AU - Zumbo, Paul
AU - Espinosa-Carrasco, Gabriel
AU - Shakiba, Mojdeh
AU - Sanchez-Rivera, Francisco J.
AU - Socci, Nicholas D.
AU - Trivedi, Prerak
AU - Lowe, Scott W.
AU - Lauer, Peter
AU - Mohibullah, Neeman
AU - Viale, Agnes
AU - DiLorenzo, Teresa P.
AU - Betel, Doron
AU - Schietinger, Andrea
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2/3
Y1 - 2022/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120356201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120356201&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04248-x
DO - 10.1038/s41586-021-04248-x
M3 - Article
C2 - 34847567
AN - SCOPUS:85120356201
SN - 0028-0836
VL - 602
SP - 156
EP - 161
JO - Nature
JF - Nature
IS - 7895
ER -