CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis

X Xu, P Dennett, J Zhang, A Sherrard, Y Zhao… - Journal of Experimental …, 2023 - rupress.org
X Xu, P Dennett, J Zhang, A Sherrard, Y Zhao, T Masubuchi, JD Bui, X Chen, E Hui
Journal of Experimental Medicine, 2023rupress.org
CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and
CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28
costimulatory signaling is well-established, the mechanism has remained unclear. Here, we
report that human T cells acquire antigen-presenting-cell (APC)–derived B7 ligands and
major histocompatibility complex (MHC) via trogocytosis through CD28: B7 binding.
Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell …
CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28 costimulatory signaling is well-established, the mechanism has remained unclear. Here, we report that human T cells acquire antigen-presenting-cell (APC)–derived B7 ligands and major histocompatibility complex (MHC) via trogocytosis through CD28:B7 binding. Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell-intrinsically by CTLA4, which depletes B7 ligands trogocytosed or endogenously expressed by T cells through cis-endocytosis. Extending this model to the previously proposed extrinsic function of CTLA4 in human regulatory T cells (Treg), we show that blockade of either CD28 or CTLA4 attenuates Treg-mediated depletion of APC B7, indicating that trogocytosis and CTLA4-mediated cis-endocytosis work together to deplete B7 from APCs. Our study establishes CTLA4 as a cell-intrinsic molecular sink that limits B7 availability on the surface of T cells, with implications for CTLA4-targeted therapy.
rupress.org
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