This proposal is a competitive renewal of the previous grant, AI 07289, a long term project supported by a ten year Merit Award.
The aims of this competitive renewal have been expanded from the original application to take advantage of progress in these investigations as well as in the field. These studies focus on the question of how foreign peptide epitopes are selected, and complexed by the MHC molecule for antigen presentation, and how the T cell receptor recognizes the peptide epitope in the context of MHC. The general aims are to use the techniques of immunobiology, biochemistry, molecular genetics and three dimensional structure analysis, (l) to understand the mechanism by which peptides of appropriate length and sequence are selected for and bound by the MHC presenting molecules and (2) to identify at the structural level, the features of the T cell receptor involved in recognizing these peptides in the MHC target molecules. Specifically, it is proposed to continue the studies begun in the previous grant period on the structural basis for the function of class I molecules in peptide presentation. These will include a series of related projects utilizing either three-dimensional structure analysis or in vitro, biochemical and physical-chemical procedures to probe the structural impact of MHC polymorphism, the mechanism for editing and binding peptides, and the role and interactions of chaperones in the proper folding of MHC class I complexes. These studies are relevant to peptide vaccine development. T-cell receptor function/structure analyses will be complemented by studies to determine the 3D structure of the T-cell receptor in order to understand the structural basis for the events of T-cell recognition of peptide presented by MHC, studies that are relevant to T-cell development, immunity to infectious diseases and autoimmunity.
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| Samanta, Dibyendu; Guo, Haisu; Rubinstein, Rotem et al. (2017) Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2. Mol Immunol 81:151-159 |
| Scandiuzzi, Lisa; Ghosh, Kaya; Hofmeyer, Kimberly A et al. (2014) Tissue-expressed B7-H1 critically controls intestinal inflammation. Cell Rep 6:625-32 |
| Rubinstein, Rotem; Ramagopal, Udupi A; Nathenson, Stanley G et al. (2013) Functional classification of immune regulatory proteins. Structure 21:766-76 |
| Vigdorovich, Vladimir; Ramagopal, Udupi A; Lázár-Molnár, Eszter et al. (2013) Structure and T cell inhibition properties of B7 family member, B7-H3. Structure 21:707-17 |
| Samanta, Dibyendu; Ramagopal, Udupi A; Rubinstein, Rotem et al. (2012) Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion. Proc Natl Acad Sci U S A 109:14836-40 |
| Samanta, Dibyendu; Mukherjee, Gayatri; Ramagopal, Udupi A et al. (2011) Structural and functional characterization of a single-chain peptide-MHC molecule that modulates both naive and activated CD8+ T cells. Proc Natl Acad Sci U S A 108:13682-7 |
| Wang, Li; Rubinstein, Rotem; Lines, Janet L et al. (2011) VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 208:577-92 |
| Zhan, Chenyang; Patskovsky, Yury; Yan, Qingrong et al. (2011) Decoy strategies: the structure of TL1A:DcR3 complex. Structure 19:162-71 |
| Lázár-Molnár, Eszter; Chen, Bing; Sweeney, Kari A et al. (2010) Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci U S A 107:13402-7 |
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