The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses

Nat Rev Immunol. 2011 Nov 25;11(12):852-63. doi: 10.1038/nri3108.


The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and against the T cell-intrinsic and -extrinsic functions of CTLA4.

MeSH terms

  • Animals
  • Antigen Presentation
  • CD28 Antigens / immunology
  • CTLA-4 Antigen / deficiency
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology*
  • Cells, Cultured / immunology
  • Clathrin-Coated Vesicles / immunology
  • Endocytosis
  • Humans
  • Immune Tolerance / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological
  • Protein Isoforms / immunology
  • Radiation Chimera
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • CD28 Antigens
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Protein Isoforms