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Germline-like TCR alpha chains dominate shared self-reactive T cell receptors in type 1 diabetes

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 TCR alpha chains between individuals (“public”).

ORGANISM(S): Homo sapiens

PROVIDER: GSE182870 | GEO | 2021/12/15

REPOSITORIES: GEO

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Germline-like TCR alpha chains shared between autoreactive T cells in blood and pancreas [dataset1]

Project description:How human islet antigen reactive CD4+ memory T cells (IAR T cells) from peripheral blood affect Type 1 Diabetes (T1D) progression in the pancreas is poorly understood. We identified paired alpha/beta (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 organ donors. We detected extensive TRA junction sharing between IAR T cells and pancreatic infiltrating T cells (PIT), with perfect or single mismatched TRA junction amino acid sequences comprising ~34% of unique IAR TRA junctions. PIT-matched TRA junctions were largely public, and showed significant nucleotide sequence convergence, increased use of germline-encoded residues in epitope engagement, and a potential for cross-reactivity. The link with T cells in the pancreas implicates autoreactive IAR T cells with shared TRA junctions in the prediabetic and new onset phases of T1D progression.

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Germline-like TCR alpha chains dominate shared self-reactive T cell receptors in type 1 diabetes

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Project description:Islet-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects are thought to be involved in disease pathogenesis, but full understanding of their role is complicated by their presence also in blood of in healthy subjects. To elucidate their role in T1D, we have combined flow cytometry and single cell RNA sequencing (RNA-seq) techniques to link prior antigen exposure, inferred from expanded TCR clonotypes, and functional capacities of islet antigen-reactive CD4+ memory T cells. We find that cells activated by pooled peptides from immunodominant islet antigens showed significantly higher clonotype sharing within recent onset T1D subjects than in healthy individuals, consistent with in vivo T cell expansion during disease progression. There was no clonotype sharing between donors, indicating a predominance of TCRs with distinct or “private” specificities. Expanded clonotypes could be stable, as one was detected at repeat visits by spanning more than a year by one subject. We identified distinct IGRP peptides as the targets of expanded TCR clonotypes from two T1D subjects, thereby implicating this molecule as a trigger for CD4+ T cell expansion during T1D. Transcriptome profiles of cells from T1D and healthy subjects differed, particularly in cells having the most highly expanded TCR clonotypes. As a group, cells with the most highly expanded TCR clonotypes showed Th2-like phenotypes, but at the single cell level there was phenotypic heterogeneity within and between donors. Our findings demonstrate unique specificities and phenotypes of individual islet-reactive CD4+ memory T cells that have expanded during disease progression.

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