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 #
1R01AI045051-01
Application #
2835440
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Collier, Elaine S
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Exley, Mark A; Wilson, Brian; Balk, Steven P (2010) Isolation and functional use of human NKT cells. Curr Protoc Immunol Chapter 14:Unit 14.11
Blauvelt, Marisa L; Khalili, Maryam; Jaung, Weonjoo et al. (2008) Alpha-S-GalCer: synthesis and evaluation for iNKT cell stimulation. Bioorg Med Chem Lett 18:6374-6
Exley, Mark A; Hou, Runhua; Shaulov, Angela et al. (2008) Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. Eur J Immunol 38:1756-66
Montoya, Carlos J; Catano, Juan C; Ramirez, Zoraida et al. (2008) Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype. Clin Immunol 127:1-6
Yang, Otto O; Wilson, S Brian; Hultin, Lance E et al. (2007) Delayed reconstitution of CD4+ iNKT cells after effective HIV type 1 therapy. AIDS Res Hum Retroviruses 23:913-22
Montoya, Carlos J; Pollard, David; Martinson, Jeffrey et al. (2007) Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology 122:1-14
Montoya, Carlos J; Jie, Hyun-Bae; Al-Harthi, Lena et al. (2006) Activation of plasmacytoid dendritic cells with TLR9 agonists initiates invariant NKT cell-mediated cross-talk with myeloid dendritic cells. J Immunol 177:1028-39
Nieuwenhuis, Edward E S; Gillessen, Silke; Scheper, Rik J et al. (2005) CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 14:250-8
Arrizabalaga, Gustavo; Ruiz, Felix; Moreno, Silvia et al. (2004) Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a sodium/hydrogen exchanger in calcium regulation. J Cell Biol 165:653-62
Thomas, Seddon Y; Hou, Runhua; Boyson, Jonathan E et al. (2003) CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J Immunol 171:2571-80

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