The ablation of pancreatic beta cells by autoreactive T cells seen in Type I diabetes is thought to be the result of a complex interplay between genetic and environmental factors. In human disease, incomplete concordance between identical twins suggests that factors other than genetics contribute to disease progression. (1) Recent studies of autoimmune diseases in humans and mice have demonstrated quantitative and/or qualitative defects in an unusual population of CD4+ or CD4-CD8-, NKRP1+ T cells that use an invariant TCRalpha (Valpha24JalphaQ) chain paired with a restricted repertoire of TCR Vbeta chains. (2)(3) These cells have the unique capability to secrete large amounts of interleukin-4 (IL-4) without prior IL-4 priming, and as such, are a candidate source of early IL-4 thought to be important in biasing a T cell response towards a Th2 phenotype, and away from the pro- inflammatory Th1 phenotype seen in Type 1 diabetes. The ligand recognized by these potentially regulatory T cells is CD1d. (4) The striking conservation of CD1d and the TCRs used by invariant T cells between mice and humans indicate an important function for these cells during an immune response. In a study of identical twins discordant for Type 1 diabetes we demonstrated that there were reduced numbers of invariant T cells and a striking defect in IL-4 production in clones derived from the diabetic siblings. We hypothesize that IL-4 specific changes in TCR signaling pathways occurred during the progression to Type 1 diabetes. We propose to use Valpha24JalphaQ T cell clones raised from discordant twins to compare and contrast signaling events and gene expression patterns occurring after TCR engagement in order to identify the reason(s) for the defect in IL-4 secretion seen in the diabetic twin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045051-05
Application #
6632073
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ridge, John P
Project Start
1999-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2005-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$265,580
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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