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Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II¹

Bitao Liang^*, Craig Workman, Janine Lee^*, Claude Chew^*, Benjamin M. Dale^*, Lucrezia Colonna^*, Marcella Flores^*, Nianyu Li, Edina Schweighoffer, Steven Greenberg^*, Victor Tybulewicz, Dario Vignali and Raphael Clynes^2,*

^* Departments of Microbiology, Pharmacology and Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032; St. Jude’s Children’s Hospital, Memphis TN 38105; and Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom

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 FcR 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by National Institutes of Health, National Cancer Institute R01 CA94037 (to R.C.) and T32 HL 072739 (to B.L.).

² Address correspondence and reprint requests to Dr. Raphael Clynes, Columbia University, P and S Building, Room 8-510, 630 West 168th Street, New York, NY 10032. E-mail address: rc645{at}columbia.edu

³ Abbreviations used in this paper: DC, dendritic cell; LAG-3, lymphocyte activation gene-3; MHC II, MHC class II; BMDC, bone marrow-derived DC; WT, wild type; Treg, regulatory T cell.

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