CD1d is an MHC class I-like protein and the antigen presenting molecule recognized by a conserved population of CD4+ or CD4-CD8- (double negative), NKR-P1 plus T cells that use an invariant TCRalpha chain and produce large amounts of IL-4 and IFNgamma (invariant NKR-P1 T cells). Recent studies in humans and mice have indicated a role for invariant NKR-P1 T cells in augmenting Th1 immune responses. The loss of invariant NKR-P1 T cells and defects in IL-4 production by these cells have been reported in several autoimmune diseases, including human type 1 diabetes. Invariant NKR-P1 T cells can also mediate anti-tumor effects of IL-12 and loss of these cells in Cd1d knockout mice can increase susceptibility to viral infection. These observations indicate that a physiological function for CD1d reactive invariant NKR-P1 T cells is to augment cell mediated Th1 immunity in response to appropriate immunological stimuli, with the autoimmune pathology linked to these cells reflecting this same Th1 inducing activity. The objectives of this proposal are to test this hypothesis and determine the mechanisms through which invariant NKR-P1 T cells modulate immune responses.
Aim 1 will assess invariant NKR-P1 T cell function in humans prospectively in a series of normal donors versus autoimmune patients and patients enrolled in an IL- 12 clinical trial.
Aim 2 will assess human CD1d+ T cells, B cells, and/or monocytes as target cells for invariant NKR-P1 T cells and for a novel population of bone marrow derived CD1d reactive T cells we have recently isolated.
Aim 3 will assess changes in murine invariant NKR-P1 T cells in a viral infection model and, in CD1d knockout mice, will directly assess the contribution of CD1d and invariant NKR-P1 T cells to cytolytic T cell responses. The long term goals are to exploit CD1d reactive T cell populations as markers of immunological status and as therapeutic targets for drugs to boost Th1 responses (in the case of pathogens or vaccines) or suppress Th1 responses (in the setting of autoimmune disease).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042955-04
Application #
6510822
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$264,151
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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
van der Vliet, Hans J J; Wang, Ruojie; Yue, Simon C et al. (2008) Circulating myeloid dendritic cells of advanced cancer patients result in reduced activation and a biased cytokine profile in invariant NKT cells. J Immunol 180:7287-93
van Dervliet, Hans J J; Koon, Henry B; Yue, Simon C et al. (2007) Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer. Clin Cancer Res 13:2100-8
Yue, Simon C; Shaulov, Angela; Wang, Ruojie et al. (2005) CD1d ligation on human monocytes directly signals rapid NF-kappaB activation and production of bioactive IL-12. Proc Natl Acad Sci U S A 102:11811-6
Balk, Steven P; Ko, Yoo-Joung; Bubley, Glenn J (2003) Biology of prostate-specific antigen. J Clin Oncol 21:383-91
Exley, M A; Bigley, N J; Cheng, O et al. (2001) CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus. J Leukoc Biol 69:713-8
Sonoda, K H; Faunce, D E; Taniguchi, M et al. (2001) NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J Immunol 166:42-50
Exley, M; Garcia, J; Wilson, S B et al. (2000) CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes. Immunology 100:37-47
Sonoda, K H; Exley, M; Snapper, S et al. (1999) CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site. J Exp Med 190:1215-26