Autoreactive T cell receptors with shared germline-like α chains in type 1 diabetes.

Peter S Linsley,Janice Chen,Vivian H Gersuk,Cate Speake,Mario G Rosasco,Colin O’Rourke,Gerald T Nepom,Todd M Brusko,Elisa Balmas,Kaitlin J Flynn,Howard R Seay,William W Kwok,Alex K Hu,Fariba Barahmand-Pour-Whitman,Karen Cerosaletti,Elisavet Serti,Hannah A Deberg,Carla J Greenbaum,Keshav Motwani

doi:10.1172/jci.insight.151349

Peter S Linsley, Janice Chen + Show 17 more

Open Access

https://doi.org/10.1172/jci.insight.151349

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Abstract

Human islet antigen reactive CD4+ memory T cells (IAR T cells) play a key role in the pathogenesis of autoimmune type 1 diabetes (T1D). Using single-cell RNA sequencing (scRNA-Seq) to identify T cell receptors (TCRs) in IAR T cells, we have identified a class of TCRs that share TCRα chains between individuals (“public” chains). We isolated IAR T cells from blood of healthy, new-onset T1D and established T1D donors using multiplexed CD154 enrichment and identified paired TCRαβ sequences from 2767 individual cells. More than a quarter of cells shared TCR junctions between 2 or more cells (“expanded”), and 29/47 (~62%) of expanded TCRs tested showed specificity for islet antigen epitopes. Public TCRs sharing TCRα junctions were most prominent in new-onset T1D. Public TCR sequences were more germline like than expanded unique, or “private,” TCRs, and had shorter junction sequences, suggestive of fewer random nucleotide insertions. Public TCRα junctions were often paired with mismatched TCRβ junctions in TCRs; remarkably, a subset of these TCRs exhibited cross-reactivity toward distinct islet antigen peptides. Our findings demonstrate a prevalent population of IAR T cells with diverse specificities determined by TCRs with restricted TCRα junctions and germline-constrained antigen recognition properties. Since these “innate-like” TCRs differ from previously described immunodominant TCRβ chains in autoimmunity, they have implications for fundamental studies of disease mechanisms. Self-reactive restricted TCRα chains and their associated epitopes should be considered in fundamental and translational investigations of TCRs in T1D.

Highlights

Human islet antigen reactive CD4+ memory T cells (IAR T cells) are widely studied for their role in β cell destruction and as therapeutic targets and biomarkers [1,2,3,4,5,6] of type 1 diabetes (T1D)
A defining characteristic of all T cells is the ability of their T cell receptors (TCRs) to recognize antigenic peptides presented in the context of major histocompatibility (MHC) molecules
To investigate the expansion of IAR T cells, we extended our previous comparisons of IAR T cells from T1D and healthy controls (HCs) patients [26]

Summary

Introduction

Human islet antigen reactive CD4+ memory T cells (IAR T cells) are widely studied for their role in β cell destruction and as therapeutic targets and biomarkers [1,2,3,4,5,6] of type 1 diabetes (T1D). Each T cell expresses a distinct TCR clonotype, most commonly comprising TCRα and β chains (TRA and TRB, respectively) created by stochastic V(D)J recombination of germline encoded gene segments. This process has the potential to be extremely diverse, with a vast potential repertoire size [10, 11], which is further expanded because of random deletion and insertion of nucleotides at the recombination sites. Expansion of cells with self-reactive clonotypes supports their role in driving and propagating disease in an autoimmune disease model [13]

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