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

Science. 2011 Apr 29;332(6029):600-3. doi: 10.1126/science.1202947. Epub 2011 Apr 7.

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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • B7-1 Antigen / immunology*
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / immunology*
  • B7-2 Antigen / metabolism
  • CD28 Antigens / immunology*
  • CHO Cells
  • CTLA-4 Antigen
  • Cricetinae
  • Cricetulus
  • Dendritic Cells / immunology
  • Endocytosis*
  • Humans
  • Jurkat Cells
  • Ligands
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Ovalbumin / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Antigens, CD
  • B7-1 Antigen
  • B7-2 Antigen
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Ligands
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Ovalbumin