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

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

PROVIDER: PRJNA758093 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15629400.fastq.gz	Fastqsanger.gz
	SRR15629500.fastq.gz	Fastqsanger.gz
	SRR15629600.fastq.gz	Fastqsanger.gz
	SRR15629700.fastq.gz	Fastqsanger.gz
	SRR15629800.fastq.gz	Fastqsanger.gz

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

Project description: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”).

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Self-reactive germline-like TCR alpha chains shared between blood and pancreas.

Project description:Human islet antigen reactive CD4 + memory T cells (IAR T cells) from peripheral blood have been studied extensively for their role in the pathogenesis of autoimmune type 1 diabetes (T1D). However, IAR T cells are rare, and it remains poorly understood how they affect T1D progression in the pancreas. Using single cell RNA-sequencing coupled with a multiplexed activation induced marker (AIM) enrichment assay, we identified paired TCR 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. Using TCR sequences as barcodes, we measured infiltration of IAR T cells from blood into pancreas of organ donors with and without T1D. We detected extensive TCR sharing between IAR T cells from peripheral blood and pancreatic infiltrating T cells (PIT), with perfectly matched or single mismatched TRA junctions and J gene regions, comprising ~ 34% of unique IAR TCRs. PIT-matching IAR T cells had public TRA chains that showed increased use of germline-encoded residues in epitope engagement and a propensity for cross-reactivity. The link with T cells in the pancreas implicates autoreactive IAR T cells with shared TRA junctions and increased levels in blood with the prediabetic and new onset phases of T1D progression.

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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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Project description:MS/MS characterisation data of the publication: Mild anChemoselective, Light-Driven Post-Translational Editing Allows Installation of Reactive Side Chains into Proteins.

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