2022年新着論文 17　免疫制御学分野、細胞情報学分野、発生生物学分野から論文が発表されました

Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity

Immunity. 2022 May 10;55(5):912-924.e8. doi: 10.1016/j.immuni.2022.03.013. Epub 2022 Apr 11.

Authors

Takumi Maruhashi¹, Daisuke Sugiura¹, Il-Mi Okazaki², Kenji Shimizu¹, Takeo K Maeda³, Jun Ikubo³, Harunori Yoshikawa⁴, Katsumi Maenaka⁵, Naozumi Ishimaru⁶, Hidetaka Kosako⁴, Tatsuya Takemoto⁷, Taku Okazaki⁸

Affiliations

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; Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
³ Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁴ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁵ Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
⁶ Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
⁷ Laboratory of Embryology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁸ 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.

PMID: 35413245
DOI: 10.1016/j.immuni.2022.03.013

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.

Keywords: FGL1; LAG-3; MHC class II; T cell; autoimmunity; cancer immunotherapy; co-receptor; immune checkpoint; ligand; type 1 diabetes.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Cited by 5 articles

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