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

Sofia V. Gearty, Friederike Dündar, Paul Zumbo, Gabriel Espinosa-Carrasco, Mojdeh Shakiba, Francisco J. Sanchez-Rivera, Nicholas D. Socci, Prerak Trivedi, Scott W. Lowe, Peter Lauer, Neeman Mohibullah, Agnes Viale, Teresa P. DiLorenzo, Doron Betel () and Andrea Schietinger ()
Additional contact information
Sofia V. Gearty: Memorial Sloan Kettering Cancer Center
Friederike Dündar: Weill Cornell Medicine
Paul Zumbo: Weill Cornell Medicine
Gabriel Espinosa-Carrasco: Memorial Sloan Kettering Cancer Center
Mojdeh Shakiba: Memorial Sloan Kettering Cancer Center
Francisco J. Sanchez-Rivera: Memorial Sloan Kettering Cancer Center
Nicholas D. Socci: Memorial Sloan Kettering Cancer Center
Prerak Trivedi: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center
Peter Lauer: Aduro Biotech
Neeman Mohibullah: Memorial Sloan Kettering Cancer Center
Agnes Viale: Memorial Sloan Kettering Cancer Center
Teresa P. DiLorenzo: Albert Einstein College of Medicine
Doron Betel: Weill Cornell Medicine
Andrea Schietinger: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 602, issue 7895, 156-161

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-021-04248-x

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