Journal
NATURE
Volume 602, Issue 7895, Pages 156-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-04248-x
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Funding
- NIH [T32GM007739]
- NIH NIDDK [F30DK122691]
- NIH NCI [DP2CA225212]
- Lloyd Old STAR Award of the Cancer Research Institute
- Josie Robertson Foundation
- MSKCC Core Grant [P30CA008748]
- Weill Cornell Medicine Core Laboratories Center
- NIH NIAID [R01AI123730]
- MSKCC TROT programme [5T32CA160001]
- GMTEC Postdoctoral Researcher Innovation Grant
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
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CD8 T cell-mediated autoimmune diseases are caused by the breakdown of self-tolerance mechanisms. This study identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node, which continuously produces autoimmune mediators that migrate to the pancreas and destroy beta-cells. Strategies targeting this autoimmune progenitor pool could emerge as novel immunotherapeutic interventions for type 1 diabetes.
CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells(1). 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, beta-cell-specific CD8 T cells destroy insulin-producing beta-cells. Here we followed the fate of beta-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 beta-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 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 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.
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