Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

OS Qureshi, Y Zheng, K Nakamura, K Attridge… - Science, 2011 - science.org
OS Qureshi, Y Zheng, K Nakamura, K Attridge, C Manzotti, EM Schmidt, J Baker, LE Jeffery…
Science, 2011science.org
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell
immune responses whose mechanism of action is the subject of debate. CTLA-4 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. After 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 …
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 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. After 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 T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which 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.
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