T cells bearing ?? T cell receptors (TCRs) are responsible for driving specific immune responses against invading organisms and, in the case of autoimmunity, against self. The TCRs on these cells react with antigenic peptides bound to major histocompatibility complex proteins (MHC). The reasons for the bias of TCRs for interaction with MHC has long been debated, however, recent evidence suggests that evolution has selected for amino acids at certain positions on TCRs that have a built in likelihood of engaging MHC. This project will investigate the nature of the sites on MHC that are the reciprocal of those on TCRs i.e. that consistently engage the evolutionarily selected MHC-reacting amino acids of TCRs. Although evidence suggests that TCRs have the ability to react generically with MHC, individual TCRs are certainly specific for particular types and alleles of MHC proteins, as witnessed by the MHC allele restriction conferred on T cells during positive selection in the thymus. This project will study the structural bases for MHC allele specificity on the part of T cells. Regulatory T cells prevent immune responses against certain tissues in the body. It is thought that they do this by reacting with MHC bound to self-peptides that are present in the tissue at issue. In spite of much work, little is known about the endogenous peptides that are recognized in normal mice by endogenous regulatory T cells. Mice and methods developed in this Project will be used, in conjunction with MHC/peptide libraries, to identify self-peptides that are recognized by regulatory T cells. Overall, this Project will investigate various aspects o the TCR/MHC/peptide interaction. It will thus provide a firmer basis for our understanding of the structural bases for TCR interaction with generic and particular MHC proteins and illuminate the long mysterious process of T cell positive selection. Studies will also establish the nature of sel-peptides recognized in association with MHC by regulatory T cells, a discovery which will help understanding of the mode of action of regulatory T cells and perhaps improve ability to manipulate these cells in vivo.

Public Health Relevance

The immune response protects us against infections and, in certain unfortunate cases, causes autoimmune diseases such as rheumatoid arthritis and Type 1 diabetes. T cells are crucial components of immune responses, however, in order to act they must recognize that an invader has entered the body and needs to be destroyed. T cells use special receptors to recognize the arrival of the invader. The experiments in this Project will study the nature of these receptors with the hope that such knowledge will help us design better vaccines and better ways of preventing autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI018785-30A1
Application #
8761872
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Chiodetti, Lynda
Project Start
1982-05-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
30
Fiscal Year
2014
Total Cost
$410,240
Indirect Cost
$150,382
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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
Noges, Laura E; White, Janice; Cambier, John C et al. (2016) Contamination of DNase Preparations Confounds Analysis of the Role of DNA in Alum-Adjuvanted Vaccines. J Immunol 197:1221-30
Rubtsov, Anatoly V; Rubtsova, Kira; Kappler, John W et al. (2015) CD11c-Expressing B Cells Are Located at the T Cell/B Cell Border in Spleen and Are Potent APCs. J Immunol 195:71-9
Rubtsova, Kira; Marrack, Philippa; Rubtsov, Anatoly V (2015) Sexual dimorphism in autoimmunity. J Clin Invest 125:2187-93
Atif, Shaikh M; Nelsen, Michelle K; Gibbings, Sophie L et al. (2015) Cutting Edge: Roles for Batf3-Dependent APCs in the Rejection of Minor Histocompatibility Antigen-Mismatched Grafts. J Immunol 195:46-50
Rubtsova, Kira; Rubtsov, Anatoly V; Cancro, Michael P et al. (2015) Age-Associated B Cells: A T-bet-Dependent Effector with Roles in Protective and Pathogenic Immunity. J Immunol 195:1933-7
Jin, Niyun; Wang, Yang; Crawford, Frances et al. (2015) N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes. Proc Natl Acad Sci U S A 112:13318-23
Rubtsova, Kira; Marrack, Philippa; Rubtsov, Anatoly V (2015) TLR7, IFNγ, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cell Immunol 294:80-3
David, A; Trigunaite, A; Macleod, M K et al. (2014) Intrinsic autoimmune capacities of hematopoietic cells from female New Zealand hybrid mice. Genes Immun 15:153-61
Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42

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