TCR recognition of peptide antigens bound and presented by MHC proteins is a cornerstone of cellular immunity. Although structural knowledge of TCR-pMHC interactions has surged over the past decade, there are significant gaps in our understanding of how TCRs engage pMHC and achieve the key immunological phenomena of specificity, cross-reactivity, and MHC restriction. Indeed, recent years have seen controversy regarding the determinants of TCR recognition properties, such as the extent to which TCRs are evolutionarily biased towards engaging MHC proteins and how such bias may be influenced by other factors. Additionally, structural immunologists are focusing increased attention on molecular motion, which has been shown to have complex and poorly understood influences on specificity, cross-reactivity, and potentially even signaling. Beyond informing basic immunology, an improved understanding of how TCRs achieve specificity, cross-react, and signal is crucial as antigenic epitopes and TCRs begin to be used in clinical settings. This competitive renewal proposal describes an ambitious plan to address key questions related to the issues above, with goals of not only uncovering fundamental principles, but also advancing the development of TCR and pMHC-based therapeutics. There are two broadly complementary specific aims. The first will determine how the distribution of TCR-pMHC binding energy is shaped by evolutionary and non-evolutionary forces. A range of experimental approaches will be applied, including double mutant cycle analyses, X-ray crystallography, protein engineering, and structural bioinformatics.
The second aim will establish the role and impact of molecular motion in TCR and pMHC recognition. A range of approaches will again be used, including NMR, fluorescence, and computation. Throughout both aims, a number of novel hypotheses will be tested, including our hypothesis that the TCR binding site has evolved a structural and energetic permissiveness that permits the receptor to adjust to the unique chemistry present in each interface. We will also test the hypotheses that peptide modulation of MHC dynamics influences NK receptor binding, and that alterations in TCR dynamics upon binding contribute to T cell signaling.

Public Health Relevance

Recognition of peptide/MHC complexes by T cell receptors and other molecules of the immune system is central to immunity. Yet our understanding of the physical mechanisms of recognition and how they translate into function remains rudimentary. This project will use a range of structural and biophysical tools to study immune recognition, improving our understanding of cellular immunity and facilitating the development of immunologically-based therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM067079-10
Application #
8743692
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Marino, Pamela
Project Start
2003-02-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Ayres, Cory M; Scott, Daniel R; Corcelli, Steven A et al. (2016) Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity. Sci Rep 6:25070
Riley, Timothy P; Singh, Nishant K; Pierce, Brian G et al. (2016) Computational Reprogramming of T Cell Antigen Receptor Binding Properties. Methods Mol Biol 1414:305-18
Blevins, Sydney J; Pierce, Brian G; Singh, Nishant K et al. (2016) How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire. Proc Natl Acad Sci U S A 113:E1276-85
Hellman, Lance M; Yin, Liusong; Wang, Yuan et al. (2016) Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide-MHC complexes. J Immunol Methods 432:95-101
Riley, Timothy P; Singh, Nishant K; Pierce, Brian G et al. (2016) Computational Modeling of T Cell Receptor Complexes. Methods Mol Biol 1414:319-40
Spear, Timothy T; Riley, Timothy P; Lyons, Gretchen E et al. (2016) Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability. J Leukoc Biol 100:545-57
Belden, Orrin S; Baker, Sarah Catherine; Baker, Brian M (2015) Citizens unite for computational immunology! Trends Immunol 36:385-7
Duan, Fei; Duitama, Jorge; Al Seesi, Sahar et al. (2014) Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J Exp Med 211:2231-48
Pierce, Brian G; Hellman, Lance M; Hossain, Moushumi et al. (2014) Computational design of the affinity and specificity of a therapeutic T cell receptor. PLoS Comput Biol 10:e1003478
Motozono, Chihiro; Kuse, Nozomi; Sun, Xiaoming et al. (2014) Molecular basis of a dominant T cell response to an HIV reverse transcriptase 8-mer epitope presented by the protective allele HLA-B*51:01. J Immunol 192:3428-34

Showing the most recent 10 out of 40 publications