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

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. Hui and colleagues show that CTLA4 acts in cis to deplete T cell-associated B7 ligands and that ipilimumab treatment inhibits this process to promote T cell autostimulation. This suggests a novel aspect of CTLA4 function with therapeutic implications.

Automated summary

CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands to control adaptive immune responses. In this study, it is found that human T cells acquire B7 ligands and MHC from antigen-presenting cells through trogocytosis mediated by CD28:B7 binding. CTLA4 limits this process by depleting B7 ligands through cis-endocytosis. The study also shows that blockade of CD28 or CTLA4 attenuates the depletion of B7 by regulatory T cells, suggesting a novel aspect of CTLA4 function with therapeutic implications.