Abstract
Abstract Besides antigen-specific signal from the interaction between T-cell receptor and peptide-MHC complex expressed on antigen presenting cells (APCs), the process of optimal T-cell activation and differentiation requires antigen-independent costimulatory signals. Costimulatory signals are provided by interaction between a number of activating as well as inhibitory receptors expressed on T cells with specific ligands expressed on APCs. The balance between activating and inhibitory signals critically controls the mammalian immune responses. Therefore, understanding the mechanisms and designing corrective therapeutics involving T-cell costimulation are imperative in both infectious as well as autoimmune diseases. TIGIT (T cell immunoglobulin and ITIM domain), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or PVR, that are over-expressed on certain tumors, inhibits activation of T and NK cells. Several biophysical studies, including X-ray crystallography suggest that TIGIT may exist in its monomeric as well as dimeric forms. Based on the structural and biochemical studies, we mapped the nectin-binding interface on TIGIT. Interestingly, structure-guided mutations that disrupt the interaction between nectin-2 and TIGIT also limit the homodimerization of TIGIT in solution. Our data provide structural insights into how TIGIT recognizes a cell-adhesion molecule nectin-2 to execute immunoregulatory function.
Published Version
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