Antigen recognition by T lymphocytes is mediated by diverse cell-surface glycoproteins known as T-cell receptors (TCRs) which are composed of alpha and beta (or gamma and delta) chains. In addition to antigenic peptides bound to MHC, alpha/beta TCRs interact with glycolipids presented by CD1 and with a class of disease-causing major subset of human gamma/delta T-cells (V-gamma-2/V-delta-2) recognizes small, aliphatic monoalkyl phosphate antigens from Mycobacterium. Besides conventional alpha/beta and gamma/delta T-cells, the T-cell compartment includes natural killer (NK) T-cells. NK T-cells express NK inhibitory receptors that mediate self-recognition by binding MHC class I. These cells also express TCRs that recognize ceramide-containing glycolipids presented by CD1.
Our aim i s to elucidate the structural basis for three key aspects of antigen recognition by alpha/beta, gamma/delta and NK T-cells: Determination of the crystal structures of representative TCR beta chain-Sag and SAG-MHC complexes in order to precisely define the diverse strategies that bacterial SAGs have evolved for binding TCR and MHC molecules. The investigator previously determined the structures of a mouse TCR beta chain (VB8.2) complexed with staphylococcal enterotoxins B and C3 (SEB, SEC3). We will now determine the structures of a human TCR beta chain (VB2.1) complexed with toxic shock syndrome toxin-1 (TSST-1) and streptococcal pyrogenic exotoxin C (SPEC). We will also determine the structure of SEC3 complexed with HLA-DR1. This study will then be extended to SEA, SED and SPEC which, unlike SEC3, cross-link MHC molecules on APCs. Determination of the structural basis for antigen recognition by human V-gamma-2/V-delta-2 TCRs. We have recently solved the structure of the TCR V delta domain and shown that it incorporates key structural elements of both antibody and alpha/beta TCR V regions. We will now extend these studies to an associated V-gamma-2/V-delta-2 TCR reactive with non-peptide prenyl pyrophosphates. 3. Determination of the structural basis for self-MHC and CD1 recognition by NK T-cells. We have crystallized a complex between the NK inhibitory receptor Ly-49A and its MHC class I ligand and a structure determination is underway. We will also express soluble forms of a canonical V alpha 14-J alpha 281/V beta 8.2 NK TCR for use in direct binding and co-crystallization experiments with specific CD1/glycolipid antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI036900-09
Application #
6650775
Study Section
Immunobiology Study Section (IMB)
Program Officer
Kehn, Patricia J
Project Start
1995-09-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
9
Fiscal Year
2003
Total Cost
$333,000
Indirect Cost
Name
University of MD Biotechnology Institute
Department
Type
Organized Research Units
DUNS #
603819210
City
Baltimore
State
MD
Country
United States
Zip Code
21202
Yang, Xinbo; Chen, Guobing; Weng, Nan-Ping et al. (2017) Structural basis for clonal diversity of the human T-cell response to a dominant influenza virus epitope. J Biol Chem 292:18618-18627
Chen, Guobing; Yang, Xinbo; Ko, Annette et al. (2017) Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8+ TCR Repertoires to Immunodominant Viral Antigens. Cell Rep 19:569-583
Li, Yili; Pierce, Brian G; Wang, Qian et al. (2015) Structural basis for penetration of the glycan shield of hepatitis C virus E2 glycoprotein by a broadly neutralizing human antibody. J Biol Chem 290:10117-25
He, Yanan; Rangarajan, Sneha; Kerzic, Melissa et al. (2015) Identification of the Docking Site for CD3 on the T Cell Receptor ? Chain by Solution NMR. J Biol Chem 290:19796-805
Yang, Xinbo; Gao, Mingming; Chen, Guobing et al. (2015) Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope. J Biol Chem 290:29106-19
Rangarajan, Sneha; Mariuzza, Roy A (2014) T cell receptor bias for MHC: co-evolution or co-receptors? Cell Mol Life Sci 71:3059-68
Holland, Stephen J; Gao, Mingming; Hirano, Masayuki et al. (2014) Selection of the lamprey VLRC antigen receptor repertoire. Proc Natl Acad Sci U S A 111:14834-9
Li, Yili; Yin, Yiyuan; Mariuzza, Roy A (2013) Structural and biophysical insights into the role of CD4 and CD8 in T cell activation. Front Immunol 4:206
Deng, Lu; Luo, Ming; Velikovsky, Alejandro et al. (2013) Structural insights into the evolution of the adaptive immune system. Annu Rev Biophys 42:191-215
Luo, Ming; Velikovsky, C Alejandro; Yang, Xinbo et al. (2013) Recognition of the Thomsen-Friedenreich pancarcinoma carbohydrate antigen by a lamprey variable lymphocyte receptor. J Biol Chem 288:23597-606

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