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A critical insulin TCR contact residue selects high affinity and pathogenic insulin specific T cells

ABSTRACT: A critical insulin TCR contact residue selects high affinity and pathogenic insulin specific T cells

PROVIDER: PRJNA580235 | ENA |

REPOSITORIES: ENA

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A critical insulin TCR contact residue selects high affinity and pathogenic insulin specific T cells

Project description:Type 1 Diabetes (T1D) is an autoimmune mediated disease that culminates in the targeted destruction of insulin producing β cells. CD4 responses in non-obese diabetic mice are dominated by InsB9-23 specificity, and mutation of the key TCR contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and T regulatory cells. Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality and pathogenicity of insulin specific T cells that develop in the absence of cognate antigen. Using single TCR system, we demonstrate that Treg development is greatly diminished in mice with Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB9-23 by both limiting the development of pathogenic T cells and supporting the selection of regulatory T cells.

2019-10-30 | GSE139544 | GEO

A Critical Insulin TCR Contact Residue Selects High-Affinity and Pathogenic Insulin-Specific T Cells.

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Leucine-973 is a Crucial Residue Differentiating Insulin and IGF-1 Receptor Signaling

Project description:Insulin and IGF-1 receptors (IR/IGF1R) are highly homologous and share similar signaling systems, but each has a unique physiological role, with IR primarily regulating metabolic homeostasis and IGF1R regulating mitogenic control and growth. Here, we show that replacement of a single amino acid at position 973, just distal to the NPEY motif in the intracellular juxtamembrane region, from leucine, which is highly-conserved in IRs, to phenylalanine, the highly-conserved homologous residue in IGF1Rs, results in decreased IRS-1-PI3K-Akt-mTORC1 signaling and increased of Shc-Gab1-MAPK-cell cycle signaling. As a result, cells expressing L973F-IR exhibit decreased insulin-induced glucose uptake, increased cell growth and impaired receptor internalization. Mice with knockin of the L973F-IR show similar alterations in signaling in vivo, and this leads to decreased insulin sensitivity, a modest increase in growth and decreased weight gain when challenged with high-fat diet. Thus, leucine973 in the juxtamembrane region of the IR acts is a crucial residue differentiating IR signaling from IGF1R signaling.

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