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

• Published in: Nature reviews. Immunology Vol. 11; no. 12; pp. 852 - 863
• Main Authors: Walker, Lucy S. K., Sansom, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2011; Nature Publishing Group
• Subjects: 38; 631/250/1619/554/1775; 631/250/2152/1566; Animals; Antigen Presentation; Biomedicine; CD28 Antigens - immunology; Cells; Cells, Cultured - immunology; Clathrin-Coated Vesicles - immunology; CTLA-4 Antigen - deficiency; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytotoxicity; Data processing; Endocytosis; Genetic aspects; Health aspects; Humans; Immune response; Immune system; Immune Tolerance - immunology; Immunology; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Interleukin-2; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Models, Immunological; Physiological aspects; Protein Isoforms - immunology; Proteins; Radiation Chimera; review-article; Signal Transduction - immunology; T cells; T-Lymphocytes, Regulatory - immunology; Thymus gland; Transforming growth factors; United Kingdom
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri3108

Key Points Cytotoxic T lymphocyte antigen 4 (CTLA4) and its homologue CD28 are crucial T cell proteins associated with immune regulation. They share the same ligands, CD80 and CD86, which are present on antigen-presenting cells (APCs). CTLA4-deficient mice suffer from fatal lymphoproliferative disease and die by 3–4 weeks of age, indicating that CTLA4 is an essential negative regulator of T cell responses. By contrast, CD28-deficient mice are immunocompromised. CTLA4 is a highly endocytic receptor that undergoes both recycling to the plasma membrane and degradation in lysosomes. The cytoplasmic domain, which is required for these functions, is highly conserved in mammals. CTLA4 is expressed by regulatory T (T Reg ) cells and activated conventional T cells. Evidence suggests that CTLA4 is important for T Reg cell suppressive function in many settings. The molecular mechanism of CTLA4 function is still undecided and a number of cell-intrinsic and cell-extrinsic mechanisms have been proposed. In vivo studies using bone marrow chimeric mice indicate that CTLA4-deficient T cells are not dysregulated in the presence of wild-type T cells. This suggests that the main non-redundant function of CTLA4 in vivo is a cell-extrinsic one. Emerging evidence suggests that one cell-extrinsic function of CTLA4 may be to downregulate CD80 and CD86 expression on APCs, thereby limiting the ability of APCs to stimulate T cells via CD28. Cytotoxic T lymphocyte antigen 4 (CTLA4) has long been known to have an important regulatory role in the immune system; however, its mechanisms of action have been the subject of considerable debate. This article reviews the strengths and limitations of the cell-intrinsic and cell-extrinsic models that have been proposed to explain the function of CTLA4. 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.