Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II

• Published in: The Journal of immunology (1950) Vol. 180; no. 9; pp. 5916 - 5926
• Main Authors: Liang, Bitao, Workman, Craig, Lee, Janine, Chew, Claude, Dale, Benjamin M, Colonna, Lucrezia, Flores, Marcella, Li, Nianyu, Schweighoffer, Edina, Greenberg, Steven, Tybulewicz, Victor, Vignali, Dario, Clynes, Raphael
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.05.2008
• Subjects: Animals; Antibodies - pharmacology; Antigens, CD - immunology; Antigens, CD - metabolism; CD4 Antigens - immunology; CD4 Antigens - metabolism; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; Immunologic Capping - drug effects; Immunologic Capping - immunology; Lymphocyte Activation Gene 3 Protein; Mice; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - immunology; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Receptors, IgG - immunology; Receptors, IgG - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.9.5916

Lymphocyte activation gene-3 (LAG-3) is a CD4-related transmembrane protein expressed by regulatory T cells that binds MHC II on APCs. It is shown in this study that during Treg:DC interactions, LAG-3 engagement with MHC class II inhibits DC activation. MHC II cross-linking by agonistic Abs induces an ITAM-mediated inhibitory signaling pathway, involving FcgammaRgamma and ERK-mediated recruitment of SHP-1 that suppresses dendritic cell maturation and immunostimulatory capacity. These data reveal a novel ITAM-mediated inhibitory signaling pathway in DCs triggered by MHC II engagement of LAG-3, providing a molecular mechanism in which regulatory T cells may suppress via modulating DC function.