To identify the mechanism of action of co-inhibitory LAG-3 on CD4+ T cells, Maruhashi et al. performed cell binding assays with the extracellular domain while varying covalent peptide:MHC (pMHC) expression and screening for functional effectors. Stability of the pMHC complex was the primary determinant of LAG-3 binding to APCs and T cell inhibition was mediated by signaling of the LAG-3 intracellular domain. Secondarily, stable but highly expressed non-cognate pMHC also partially inhibited T cell activation. In diabetic NOD mice, LAG-3 slowed disease progression by suppressing autoreactive, high-affinity, peptide-specific T cells.
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.
Author Info: (1) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (2) Division of Immune Regulation, Institute of Advanced Medical
Author Info: (1) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (2) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (3) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (4) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (5) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (6) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. (7) Division of Immune Regulation, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan. tokazaki@genome.tokushima-u.ac.jp.
