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Single T-cell landscape identifies tissue regeneration program in murine and human regulatory T cells

ABSTRACT: Several studies over the past decade identified a subpopulation of murine regulatory T cells (Tregs) which have the intrinsic capacity to promote tissue homeostasis and, upon damage, enhance tissue regeneration and re-organization. In humans, this population of tissue regeneration-promoting Treg cells has not been identified and characterized yet. Using single-cell chromatin accessibility as well as single-cell RNA and TCR expression profiles of murine and human tissue-derived CD4 T cells, we identified the murine Treg repair signature and performed a liftover on human single T cell data. We identified a FOXP3+CCR8+HLA-DR+ population in peripheral blood, which has characteristics of human tissue Treg cells and promotes tissue regeneration and wound healing in-vitro. This population was dependent on the transcriptional regulator BATF, a factor that also drives the development of tissue regeneration-promoting Treg cells in the murine system. Human CCR8+HLA-DR+ Treg cells could be used as a novel T-cell product to promote tissue repair in regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE156112 | GEO | 2021/03/25

REPOSITORIES: GEO

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Project description:HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory arthritides, including in rheumatoid arthritis (RA) and Lyme arthritis (LA). In the current study, we identified HLA-DR-presented self-peptides (T cell epitopes) in ST, synovial fluid mononuclear cells (SF), and peripheral blood mononuclear cells (PB) from five patients with RA and eight with LA. Altogether, from 22 samples, 1,532 non-redundant HLA-DR-presented peptides were identified that were derived from 778 source proteins. Moreover, as the study progressed, application of newer, high sensitivity LC-MS instruments resulted in the identification of larger numbers of HLA-DR-presented peptides. Surprisingly, the source proteins for HLA-DR-presented peptides were as likely to have intracellular as extracellular locations. Although the number of peptides identified was greater in ST than in SF or PB, 68% of the peptides identified in SF were found in ST, and 55% of the peptides in PB were found in ST. Two RA patients had the same HLA-DR genotype (DRB1*0401 and 0101), and 44% of the peptides identified in these two patients were the same. In contrast, among the patients with RA or LA who had no shared HLA-DR alleles, only 6% of the peptides were the same. In the RA patients, HLA-DR-presented peptides were identified from source proteins that are thought to serve as potential autoantigens: collagen, enolase, fibrinogen, fibronectin, immunoglobulin and vimentin. Interestingly, peptides from these same source proteins were also commonly found in LA patients. However, citrullinated T cell epitopes were not identified in any patient. Thus, LC-MS/MS techniques are now sensitive enough to identify large numbers of T cell epitopes from tissue or fluids in individual patients. Importantly, analysis of SF or PB allowed us to identify a broader range of HLA-DR-presented self-peptides from individual patients and from patients seen earlier in the disease.

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Single T-cell landscape identifies tissue regeneration program in murine and human regulatory T cells

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