Abstract
Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell-mediated destruction of pancreatic β cells. We have previously shown that diabetogenic CD8 T cells in the islets of non-obese diabetic mice are phenotypically heterogeneous, but clonal heterogeneity remains relatively unexplored. Here, we use paired single-cell RNA and T-cell receptor sequencing (scRNA-seq and scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of non-obese diabetic mice. scTCR-seq demonstrates that CD8 T cells targeting the immunodominant β-cell epitope IGRP206-214 exhibit restricted TCR gene usage. scRNA-seq identifies six clusters of autoreactive CD8 T cells in the islets and six in the spleen, including memory and exhausted cells. Clonal overlap between IGRP206-214-reactive CD8 T cells in the islets and spleen suggests these cells may circulate between the islets and periphery. Finally, we identify correlations between TCR genes and T-cell clonal expansion and effector fate. Collectively, our work demonstrates that IGRP206-214-specific CD8 T cells are phenotypically heterogeneous but clonally restricted, raising the possibility of selectively targeting these TCR structures for therapeutic benefit.
Original language | English (US) |
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Article number | e202201503 |
Journal | Life science alliance |
Volume | 5 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2022 |
Funding
This work is supported by National Institutes of Health (NIH) grants DK107541 (Yi-Guang Chen), DK121747 (Yi-Guang Chen), AI125741 (W Cui), AI148403 (W Cui), DK127526 (MY Kasmani), and DK118786 (AE Ciecko); by an American Cancer Society Research Scholar Grant (W Cui); and by an Advancing a Healthier Wisconsin Endowment Grant (W Cui). MY Kasmani and AK Brown are members of the Medical Scientist Training Program at the Medical College of Wisconsin (MCW), which is partially supported by a training grant from the National Institute of General Medical Sciences (NIGMS) (T32-GM080202). This research was completed in part with computational resources and technical support provided by the Research Computing Center at MCW. NRP-V7 tetramer was obtained through the NIH Tetramer Core Facility.
ASJC Scopus subject areas
- Ecology
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Plant Science
- Health, Toxicology and Mutagenesis