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Science 332 (6029): 600-603

Copyright © 2011 by the American Association for the Advancement of Science

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

Omar S. Qureshi,1 Yong Zheng,1 Kyoko Nakamura,1 Kesley Attridge,1 Claire Manzotti,1 Emily M. Schmidt,1 Jennifer Baker,1 Louisa E. Jeffery,1 Satdip Kaur,1 Zoe Briggs,1 Tie Z. Hou,1 Clare E. Futter,2 Graham Anderson,1 Lucy S.K. Walker,1 David M. Sansom1,*

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.

1 Medical Research Council (MRC) Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham B15 2TT, UK.
2 Department of Cell Biology, University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK.

* To whom correspondence should be addressed. E-mail: d.m.sansom{at}

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