The pool of beta cell-specific CD8+ T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell ‘multipotency index’ and found that beta cell-specific CD8+ T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8+ T cells. Assessment of beta cell-specific CD8+ T cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8+ T cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8+ T cell responses and document the use of this methylation-based multipotency index for investigating human and mouse CD8+ T cell differentiation.
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The data that support the findings of this study are available from the corresponding author upon request. Whole-genome and ATAC-seq data files are available at the National Center for Biotechnology Information Gene Expression omnibus (GEO) under accession number GSE144693.
All code described is publicly available.
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We thank P. Dogra for processing samples for methylation profiling. This work was supported by the NIH (grant no. 1R01AI114442 to B.Y.), Immune Tolerance Network (grant no. UM1AI109565 to G.T.N., E.J. and B.Y.), the NIH Loan Repayment Program to C.Z., the American Lebanese Syrian Associated Charities (to B.Y.) and Assisi foundation (to B.Y.).
The authors declare no competing interests.
Editor recognition statement Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Abdelsamed, H.A., Zebley, C.C., Nguyen, H. et al. Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes. Nat Immunol 21, 578–587 (2020). https://doi.org/10.1038/s41590-020-0633-5
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