Trans-endocytosis of CD80 and CD86: a Molecular Basis for the Cell-extrinsic Function of CTLA-4

Overview

Journal Science

Specialty Science

Date 2011 Apr 9

PMID 21474713

Citations 865

Authors

Omar S Qureshi

Yong Zheng

Kyoko Nakamura

Kesley Attridge

Claire Manzotti

Emily M Schmidt

Jennifer Baker

Louisa E Jeffery

Satdip Kaur

Zoe Briggs

Tie Z Hou

Clare E Futter

Graham Anderson

Lucy S K Walker

David M Sansom

Affiliations

Soon will be listed here.

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.

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