XPR1 prevents T-cell hyperactivation through interaction with KIDINS220 for endocytic regulation of CD28 costimulation

Together with T-cell antigen receptor (TCR) engagement, CD28 costimulation is a central process that defines T-cell proliferation and differentiation relevant for immunotherapy. Here, we show that xenotropic and polytropic retrovirus receptor 1 (XPR1) regulates activation pathways and cytokine expression in CD4+ T cells by restricting CD28 costimulation. T cell-specific Xpr1 gene deletion, abrogated TCR-mediated Ca ²⁺ /NFAT signaling but enhanced AKT/mTOR pathway activation, resulting in impaired thymocyte development and hyperactivated CD4+ T cells in the periphery. Consistently, XPR1 deficiency led to increased cytokine expression in CD4+ T cells from TCR-transgenic mice and Jurkat cells. Mechanistically, XPR1 associates with kinase D-interacting substrate of 220 kDa (KIDINS220) in CD4+ T cells and regulates membrane rearrangement, CD28 surface clustering and CD28 costimulation-dependent proliferation. Utilizing membrane-permeable peptides to interfere with XPR1-KIDINS220 interactions, transcriptome analysis identified XPR1 as regulator for endocytosis and corroborated that XPR1 targeting has immunomodulatory functions for CD28 costimulation in human CD4+ T cells.