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
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
Rubtsov, Anatoly V; Rubtsova, Kira; Fischer, Aryeh et al. (2011) Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11cýýý B-cell population is important for the development of autoimmunity. Blood 118:1305-15
Scott-Browne, James P; Crawford, Frances; Young, Mary H et al. (2011) Evolutionarily conserved features contribute to ýýýý T cell receptor specificity. Immunity 35:526-35
Crawford, Frances; Stadinski, Brian; Jin, Niyun et al. (2011) Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci U S A 108:16729-34
Yin, Lei; Huseby, Eric; Scott-Browne, James et al. (2011) A single T cell receptor bound to major histocompatibility complex class I and class II glycoproteins reveals switchable TCR conformers. Immunity 35:23-33
MacLeod, Megan K L; David, Alexandria; McKee, Amy S et al. (2011) Memory CD4 T cells that express CXCR5 provide accelerated help to B cells. J Immunol 186:2889-96
MacLeod, Megan K L; McKee, Amy S; David, Alexandria et al. (2011) Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells. Proc Natl Acad Sci U S A 108:7914-9
Dai, Shaodong; Murphy, Guinevere A; Crawford, Frances et al. (2010) Crystal structure of HLA-DP2 and implications for chronic beryllium disease. Proc Natl Acad Sci U S A 107:7425-30
Marrack, Philippa; Scott-Browne, James; MacLeod, Megan K L (2010) Terminating the immune response. Immunol Rev 236:5-10
Stadinski, Brian D; Zhang, Li; Crawford, Frances et al. (2010) Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc Natl Acad Sci U S A 107:10978-83

Showing the most recent 10 out of 183 publications