RRC ID 55686
Author Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, Okazaki T.
Title LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII.
Journal Nat Immunol
Abstract The success of tumor immunotherapy targeting the inhibitory co-receptors PD-1 and CTLA-4 has indicated that many other co-receptors might be potential druggable targets, despite limited information about their functional differences. Here we identified a unique target selectivity for the inhibitory co-receptor LAG-3 that was intrinsic to its immunoregulatory roles. Although LAG-3 has been reported to recognize major histocompatibility complex (MHC) class II, it did not recognize MHC class II universally; instead, we found that it selectively recognized stable complexes of peptide and MHC class II (pMHCII). LAG-3 did not directly interfere with interactions between the co-receptor CD4 and MHC class II or between the T cell antigen receptor and MHC class II. Instead, LAG-3 preferentially suppressed T cells responsive to stable pMHCII by transducing inhibitory signals via its intracellular region. Thus, LAG-3 might function more selectively than previously thought and thereby maintain tolerance to dominant autoantigens.
Volume 19(12)
Pages 1415-1426
Published 2018-12-1
DOI 10.1038/s41590-018-0217-9
PII 10.1038/s41590-018-0217-9
PMID 30349037
MeSH Animals Antigens, CD / chemistry Antigens, CD / immunology* CD4-Positive T-Lymphocytes / immunology* Cell Line, Tumor Histocompatibility Antigens Class II / immunology* Humans Lymphocyte Activation / immunology* Mice Molecular Conformation
IF 23.53
Times Cited 25
Human and Animal Cells RAJI(RCB1647)