Germline-like TCR-α chains shared between autoreactive T cells in blood and pancreas

Peter S. Linsley (), Maki Nakayama, Elisa Balmas, Janice Chen, Fariba Barahmand-pour-Whitman, Shubham Bansal, Ty Bottorff, Elisavet Serti, Cate Speake, Alberto Pugliese and Karen Cerosaletti
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Peter S. Linsley: Benaroya Research Institute at Virginia Mason
Maki Nakayama: University of Colorado School of Medicine
Elisa Balmas: Benaroya Research Institute at Virginia Mason
Janice Chen: Benaroya Research Institute at Virginia Mason
Fariba Barahmand-pour-Whitman: Benaroya Research Institute at Virginia Mason
Shubham Bansal: Benaroya Research Institute at Virginia Mason
Ty Bottorff: Benaroya Research Institute at Virginia Mason
Elisavet Serti: Immune Tolerance Network
Cate Speake: Benaroya Research Institute at Virginia Mason
Alberto Pugliese: Arthur Riggs Diabetes & Metabolism Research Institute
Karen Cerosaletti: Benaroya Research Institute at Virginia Mason

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Human type 1 diabetes (T1D) is caused by autoimmune attack on the insulin-producing pancreatic beta cells by islet antigen-reactive T cells. How human islet antigen-reactive (IAR) CD4+ memory T cells from peripheral blood affect T1D progression in the pancreas is poorly understood. Here, we aim to determine if IAR T cells in blood could be detected in pancreas. We identify paired αβ (TRA/TRB) T cell receptors (TCRs) in IAR T cells from the blood of healthy, at-risk, new-onset, and established T1D donors, and measured sequence overlap with TCRs in pancreata from healthy, at risk and T1D organ donors. We report extensive TRA junction sharing between IAR T cells and pancreas-infiltrating T cells (PIT), with perfect-match or single-mismatch TRA junction amino acid sequences comprising ~29% total unique IAR TRA junctions (942/3,264). PIT-matched TRA junctions were largely public and enriched for TRAV41 usage, showing significant nucleotide sequence convergence, increased use of germline-encoded versus non-templated residues in epitope engagement, and a potential for cross-reactivity. Our findings thus link T cells with distinctive germline-like TRA chains in the peripheral blood with T cells in the pancreas.

Date: 2024
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DOI: 10.1038/s41467-024-48833-w

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