Maruhashi et al. analyzed the consequences of LAG-3 engagement with stable peptide–MHC class II and FGL1, and demonstrated that stable pMHC-II, but not FGL1, served as the functional ligand of LAG-3 to trigger T cell suppression. Stable pMHC-II and FGL1 bind to close, but distinct regions of LAG-3, and loss of FGL1-binding capacity did not affect the stable pMHCII-induced inhibitory function of LAG-3. Loss of stable pMHC-II, but not FGL1, binding capacity of LAG-3 recapitulated LAG-3 deficiency-mediated diabetes exacerbation in NOD mice and augmented anticancer immunity comparable to LAG-3 deficiency in C57BL/6 mice.
Contributed by Shishir Pant
ABSTRACT: Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, its functional ligand remains elusive, with distinct potential ligands identified. Here, we investigated the relative contribution of potential ligands, stable peptide-MHC class II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activity in vitro and in vivo. Binding of LAG-3 to stable pMHCII but not to FGL1 induced T cell suppression in vitro. Consistently, LAG-3 mutants lacking FGL1-binding capacity but not those lacking stable pMHCII-binding capacity retained suppressive activity in vitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacity of LAG-3 in NOD mice recapitulated diabetes exacerbation by LAG-3 deficiency. Additionally, the loss of stable pMHCII-binding capacity of LAG-3 augmented anti-cancer immunity comparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCII as a functional ligand of LAG-3 both in autoimmunity and anti-cancer immunity. Thus, stable pMHCII-LAG-3 interaction is a potential therapeutic target in human diseases.
Author Info: (1) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan. (2) Laboratory of Molecular Immunology, Institute fo
Author Info: (1) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan. (2) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan. (3) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (4) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan. (5) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (6) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (7) Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (8) Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. (9) Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan. (10) Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (11) Laboratory of Embryology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. (12) Laboratory of Molecular Immunology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. Electronic address: tokazaki@iqb.u-tokyo.ac.jp.
