Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes

Abstract

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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Fig. 1: Generation of the human CD8+ T cell DNA methylation landscape to assess beta cell-specific CD8+ T cell differentiation.
Fig. 2: Human T cell multipotency index predicts beta cell-specific CD8+ T cells to retain a degree of developmental plasticity comparable to TSCM cells.
Fig. 3: Self-reactive human CD8+ T cells acquire effector-associated epigenetic programs.
Fig. 4: Single-cell ATAC-seq profiling identifies naive and effector epigenetic programming within individual beta cell-specific CD8+ T cells.
Fig. 5: Stemness-associated DNA methylation programs are maintained during in vitro antigen-driven proliferation of human T1D-specific CD8+ T cells.
Fig. 6: Lymphoid-homing murine beta cell-specific CD8+ T cells retain phenotypic and epigenetic programs indicating developmental plasticity.
Fig. 7: Murine multipotency index predicts terminal differentiation of beta cell-specific CD8+ T cells isolated from the pancreas.

Data availability

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.

Code availability

All code described is publicly available.

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Acknowledgements

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.).

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B.Y., G.T.N., S.G.D., R.-P.S. and E.A.J. conceived the project, interpreted results and wrote the manuscript. H.A.A., C.C.Z., H.N. and R.L.R. performed the experiments, interpreted the results and helped write the manuscript. Y.F., H.E.G., J.C.C., A.H.C., M.A.M. and F.A. performed the experiments and interpreted the results. L.A.T. and D.Z. conceived the experiments and interpreted the results. E.S., C.S. and H.J. interpreted the results and coordinated the experiments. S.A., A.H.C., S.K.B., M.E.B., M.S. and S.P.R. performed the experiments.

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Correspondence to Ben Youngblood.

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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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