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

• Published in: Science (American Association for the Advancement of Science) Vol. 332; no. 6029; pp. 600 - 603
• Main Authors: Qureshi, Omar S., Zheng, Yong, Nakamura, Kyoko, Attridge, Kesley, Manzotti, Claire, Schmidt, Emily M., Baker, Jennifer, Jeffery, Louisa E., Kaur, Satdip, Briggs, Zoe, Hou, Tie Z., Futter, Clare E., Anderson, Graham, Walker, Lucy S.K., Sansom, David M.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 29.04.2011; The American Association for the Advancement of Science
• Subjects: Animals; Antibodies; Antigen presenting cells; Antigens; Antigens, CD - immunology; Antigens, CD - metabolism; B7-1 Antigen - immunology; B7-1 Antigen - metabolism; B7-2 Antigen - immunology; B7-2 Antigen - metabolism; Biological and medical sciences; Biomedical materials; Blasts; CD28 Antigens - immunology; Cell lines; Cell physiology; CHO Cells; Cricetinae; Cricetulus; CTLA-4 Antigen; cytotoxicity; Degradation; Dendritic Cells - immunology; Depletion; Endocytosis; Fundamental and applied biological sciences. Psychology; Humans; immune response; In vitro testing; Jurkat Cells; Ligands; Lymphocyte Activation; Lymphocytes; mechanism of action; Mice; Mice, Transgenic; Models, Biological; Molecular and cellular biology; Molecules; Ova; Ovalbumin - immunology; Receptors; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - metabolism; Surgical implants; T lymphocytes; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Endocytosis; Cell function
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1202947

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.