The two main antigen receptors in the jawed vertebrate immune systems that recognize antigens specifically are the B and T cell receptors. Although both receptors are generated by the same genetic mechanisms and possess an overall similar structure, they recognize antigenic ligands in fundamentally distinct ways. BCRs recognize conformational epitopes, whereas TCRs recognize small antigenic structures, often peptides derived from antigenic proteins, bound to molecules of the Major Histocompatibility Complex (MHC). The molecular basis for this MHC restriction remains essentially unknown. The proposed studies aim at testing the hypothesis that the TCR repertoire is predisposed to recognize MHC molecules in the absence of any selective pressure. Furthermore, we propose to identify the rules, if they exist, that drive this interaction. With the recent advance of the se of chimeric T cell antigen receptors as a promising form of cancer immunotherapy, an understanding of this phenomenon is absolutely fundamental. By gaining an appreciation for why and how TCRs recognize MHC, we can harness its power to better understand and modulate immune responses to infections, tumors, or transplants.

Public Health Relevance

The two main antigen receptors that can specifically recognize antigens in the jawed vertebrate immune systems are the B and T cell receptors. Although both receptors are generated by the same genetic mechanisms and possess an overall similar structure, they recognize antigenic ligands in fundamentally distinct ways. Antigen receptors on B cells recognize conformational epitopes that can be found on native proteins, whereas TCRs recognize small antigenic structures, often peptides derived from antigenic proteins, bound to molecules of the Major Histocompatibility Complex (MHC). The molecular basis for this MHC restriction remains unknown albeit intense research on the subject over the past 50 years. The proposed studies aim at testing the hypothesis that randomly generated TCR molecules are predisposed at recognizing MHC molecules. An understanding of this phenomenon is of fundamental importance for our comprehension of how the TCR recognize peptide-MHC complexes, one of the central mechanisms of immune activation, so that it can be exploited for therapeutic usage to improve human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI121761-01
Application #
9016203
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$229,920
Indirect Cost
$79,920
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Tuttle, Kathryn D; Krovi, S Harsha; Zhang, Jingjing et al. (2018) TCR signal strength controls thymic differentiation of iNKT cell subsets. Nat Commun 9:2650
Sundararaj, Srinivasan; Zhang, Jingjing; Krovi, S Harsha et al. (2018) Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function. Proc Natl Acad Sci U S A 115:E1204-E1213
Krovi, S Harsha; Gapin, Laurent (2016) Structure and function of the non-classical major histocompatibility complex molecule MR1. Immunogenetics 68:549-59
Krovi, Sai Harsha; Gapin, Laurent (2016) Revealing the TCR bias for MHC molecules. Proc Natl Acad Sci U S A 113:2809-11
Silberman, Daniel; Krovi, Sai Harsha; Tuttle, Kathryn D et al. (2016) Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors. Proc Natl Acad Sci U S A 113:E5608-17