Abstract

Insulin is an important target antigen in type 1 diabetes and a useful model antigen for ancilysis of mechanisms in antigen presentation and immune regulation. In this competing renewal application we propose experiments to further investigate antigen- prccessing mechanisms for presentation of insulin to T cells. We have identified T cells that recognize insulin presented by the nonclassical MHC class I molecule Qa-1. A major foe as of the proposal is to characterize the function of Qa-1 an its role in the immune response to insulin.
The specific aims are 1) to investigate the role of endosomal proteins in mediating disulfide reduction and antigen unfolding during antigen processing, 2) to analyze the peptide-binding behavior of the MHC class Ib molecule, Qa-1, 3) to characterize the determinant and investigate the pathway used by Qa-1-restricted T cells to recognize insulin, and 4) to investigate selection and function of insulin-specific, Qa-1- res :ricted T cells using TCR transgenic mice. This research is expected to broaden our general understanding of antigen processing and immune responses to insulin, as well as the function of Qa-1 and its human homolog, HLA-E.

  Funding Agency

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 #
5R37AI033614-18
Application #
7597149
Study Section
Special Emphasis Panel (NSS)
Program Officer
Esch, Thomas R
Project Start
1993-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
18
Fiscal Year
2009
Total Cost
$356,016
Indirect Cost

  Institution

Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Zhou, Zemin; Reyes-Vargas, Eduardo; Escobar, Hernando et al. (2016) Type 1 diabetes associated HLA-DQ2 and DQ8 molecules are relatively resistant to HLA-DM mediated release of invariant chain-derived CLIP peptides. Eur J Immunol 46:834-45
Chen, Lili; Reyes-Vargas, Eduardo; Dai, Hu et al. (2014) Expression of the mouse MHC class Ib H2-T11 gene product, a paralog of H2-T23 (Qa-1) with shared peptide-binding specificity. J Immunol 193:1427-39
Gu, Yapeng; Jensen, Peter E; Chen, Xinjian (2013) Immunodeficiency and autoimmunity in H2-O-deficient mice. J Immunol 190:126-37
Chen, Lili; Jay, David C; Fairbanks, Jared D et al. (2011) An MHC class Ib-restricted CD8+ T cell response to lymphocytic choriomeningitis virus. J Immunol 187:6463-72
Zhou, Zemin; Callaway, Kari A; Weber, Dominique A et al. (2009) Cutting edge: HLA-DM functions through a mechanism that does not require specific conserved hydrogen bonds in class II MHC-peptide complexes. J Immunol 183:4187-91
Escobar, Hernando; Crockett, David K; Reyes-Vargas, Eduardo et al. (2008) Large scale mass spectrometric profiling of peptides eluted from HLA molecules reveals N-terminal-extended peptide motifs. J Immunol 181:4874-82
Jay, David C; Reed-Loisel, Lisa M; Jensen, Peter E (2008) Polyclonal MHC Ib-restricted CD8+ T cells undergo homeostatic expansion in the absence of conventional MHC-restricted T cells. J Immunol 180:2805-14
Chen, Xinjian; Reed-Loisel, Lisa M; Karlsson, Lars et al. (2006) H2-O expression in primary dendritic cells. J Immunol 176:3548-56
Reed-Loisel, Lisa M; Sullivan, Barbara A; Laur, Oskar et al. (2005) An MHC class Ib-restricted TCR that cross-reacts with an MHC class Ia molecule. J Immunol 174:7746-52
Kambayashi, Taku; Kraft-Leavy, Jennifer R; Dauner, Joseph G et al. (2004) The nonclassical MHC class I molecule Qa-1 forms unstable peptide complexes. J Immunol 172:1661-9

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