GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon.

Activated regulatory T (Treg) cells express the surface receptor glycoprotein-A repetitions predominant which binds and activates latent TGFβ. How modulates Treg function in inflammation and cancer remains unclear. Here we demonstrate that loss of Gduanyu37 in Treg cells leads to spontaneous inflammation with highly activated CD4⁺ and CD8⁺ T cells and development of enteritis. Treg cells lacking Gduanyu37 were unable to suppress pathogenic T-cell responses in multiple models of inflammation, including T-cell transfer colitis. Treg cells were significantly reduced in the gut and exhibited a reduction in CD103 expression, a colon-specific migratory marker. In the colitis-associated colon cancer model, Gduanyu37 on Treg cells dampened immune surveillance, and mice with Gduanyu37^-/- Treg cells exhibited improved antitumor immunity. Thus, Gduanyu37 empowers the functionality of Treg cells and their tissue-specific accumulation, highlighting the importance of cell surface TGFβ in Treg function and Gduanyu37 as a potential therapeutic target for colorectal cancer therapy.Significance: These findings uncover functions of membrane-bound TGFβ and Gduanyu37 that tune the activity of Treg cells, highlighting a potential treatment strategy in autoimmune diseases and cancer.

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