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

Abstract

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.

Publication DOI: https://doi.org/10.1126/science.1202947
Divisions: College of Health & Life Sciences
Additional Information: Copyright © 2011, American Association for the Advancement of Science
Uncontrolled Keywords: antigen,antigens,CHO cells,cricetinae,cricetulus,Dendritic cells,endocytosis,Jurkat cells,ligands,Lymphocyte activation, T-Cell,biological models,ovalbumin,receptors,recombinant fusion proteins,T-lymphocyte subsets,regulatory T-lymphocytes
PURE Output Type: Article
Published Date: 2011-04-29
Accepted Date: 2011-03-14
Submitted Date: 2011-01-17
Authors: Qureshi, Omar S.
Zheng, Yong
Nakamura, Kyoko
Attridge, Kesley (ORCID Profile 0000-0003-4521-9009)
Manzotti, Claire
Schmidt, Emily M.
Baker, Jennifer
Jeffery, Louisa E.
Kaur, Satdip
Briggs, Zoe
Hou, Tie Z.
Futter, Clare E.
Anderson, Graham
Walker, Lucy S.K.
Sansom, David M.

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