Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2.

Abstract

In addition to antigen-specific stimulation of T cell receptor (TCR) by a peptide-MHC complex, the functional outcome of TCR engagement is regulated by antigen-independent costimulatory signals. Costimulatory signals are provided by an array of interactions involving activating and inhibitory receptors expressed on T cells and their cognate ligands on antigen presenting cells. T cell immunoglobulin and ITIM domain (TIGIT), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or poliovirus receptor (PVR), inhibits activation of T and NK cells. Here we report the crystal structure of the human TIGIT ectodomain, which exhibits the classic two-layer β-sandwich topology observed in other immunoglobulin super family (IgSF) members. Biophysical studies indicate that TIGIT is monomeric in solution but can form a dimer at high concentrations, consistent with the observation of a canonical immunoglobulin-like dimer interface in the crystalline state. Based on existing structural data, we present a model of the TIGIT:nectin-2 complex and utilized complementary biochemical studies to map the nectin-binding interface on TIGIT. Our data provide important structural and biochemical determinants responsible for the recognition of nectin-2 by TIGIT. Defining the TIGIT:nectin-2 binding interface provides the basis for rational manipulation of this molecular interaction for the development of immunotherapeutic reagents in autoimmunity and cancer.

DOI: 10.1016/j.molimm.2016.12.003

Cite this paper

@article{Samanta2017StructuralMA, title={Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2.}, author={Dibyendu Samanta and Haisu Guo and Rotem Rubinstein and Udupi A Ramagopal and Steven C. Almo}, journal={Molecular immunology}, year={2017}, volume={81}, pages={151-159} }