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Binding of LAG-3 to stable peptide-MHC class II limits TÂ cell function and suppresses autoimmunity and anti-cancer immunity.
- Source :
-
Immunity [Immunity] 2022 May 10; Vol. 55 (5), pp. 912-924.e8. Date of Electronic Publication: 2022 Apr 11. - Publication Year :
- 2022
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 55
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 35413245
- Full Text :
- https://doi.org/10.1016/j.immuni.2022.03.013