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- W4313373346 abstract "Abstract The major genetic determinant in susceptibility or protection from many autoimmune diseases resides in the human leukocyte antigen (HLA) region. Specific class II alleles (e.g., HLA-DQ8) increase the risk for developing type 1 diabetes (T1D), a prototypical organ specific autoimmune disease, whereas HLA-DQ6 leads to dominant protection. We hypothesize that DQ6 is protective via its ability to present insulin peptides to regulatory CD4+ T cells (Tregs), resulting in anti-inflammatory responses. We expanded insulin-specific Tregs from peripheral blood mononuclear cells (PBMCs) of DQ6+ non-diabetic individuals using an insulin peptide. Insulin-expanded Tregs were flow sorted, and paired single-cell TCR/RNA-seq (10X Genomics) was performed. Of 2,096 insulin-expanded Tregs from three DQ6+ individuals, 883 αβTCRs (42%) were present ≥2 times, and we confirmed the antigen specificity of dominant clonotypes. The single-cell RNA-seq data showed 4 clusters of Treg cells based on the expression levels of FOXP3 and IL-2RA. Additionally, we flow-sorted CD4+ T cells from the pancreatic islets of a non-diabetic DQ6+ organ donor and performed single-cell TCR sequencing. Of the 67 CD4+ cells, TCR clonotypes from three cells possessed identical TCRα chains (including CDR3 sequences) with Tregs sequenced from the PBMCs of the separate DQ6+ non-diabetic individuals. These data indicate the potential presence of insulin-specific Tregs within the pancreatic islets of non-diabetic organ donors. Our findings provide a mechanistic basis for understanding HLA-linked protection from autoimmune diabetes development and have implications for manipulating self-antigen-specific T cell responses to modify the disease course in T1D." @default.
- W4313373346 created "2023-01-06" @default.
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- W4313373346 date "2020-05-01" @default.
- W4313373346 modified "2023-09-25" @default.
- W4313373346 title "Insulin-specific regulatory T cell receptor alpha clonotypes restricted to HLA-DQ6 (DQB1*06:02) are shared between blood and islets" @default.
- W4313373346 doi "https://doi.org/10.4049/jimmunol.204.supp.224.21" @default.
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