Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell Extrinsic Function of CTLA-4

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Science  07 Apr 2011:
DOI: 10.1126/science.1202947


CTLA-4 is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 also shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. Following removal, these costimulatory ligands are degraded inside CTLA-4–expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by TCR engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation whereby CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.