Despite their critical role in certain immune responses, a clear understanding of the mechanisms by which cytotoxic T lymphocytes (CTL) bring about their effector function is presently lacking. The identification of each of the gene products that compose the cytolytic apparatus of these cells is clearly a prerequisite for a full understanding of this effector response. Thus, the overall goal of this project is to identify gene products involved in CTL-mediated lysis and to determine their roles in the cytolytic process. Progress has recently been made toward this goal by isolating and characterizing two novel CTL-specific genes; a cytokine-inducible molecule with lipase activity and the calcium-binding protein casein. This proposal reflects both molecular and genetic approaches toward expanding these initial observations. In particular, we wish to 1) elucidate the role of CTL lipase and casein in CTL function; 2) generate loss of function mutants of CTL-specific genes in CTL clones and transgenic animals using homologous recombination techniques, and 3) isolate and characterize additional cytokine-inducible and CTL-specific genes. This information will be invaluable both in understanding the role of CTL in various disease processes, and in the design of potential therapies for various autoimmune diseases in which CTL have been implicated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA056462-04
Application #
2097326
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-05-01
Project End
1997-04-30
Budget Start
1995-06-02
Budget End
1996-04-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Lowe, M E; Kaplan, M H; Jackson-Grusby, L et al. (1998) Decreased neonatal dietary fat absorption and T cell cytotoxicity in pancreatic lipase-related protein 2-deficient mice. J Biol Chem 273:31215-21
Smiley, S T; Stitt, T N; Grusby, M J (1997) Cross-linking of protein S bound to lymphocytes promotes aggregation and inhibits proliferation. Cell Immunol 181:120-6
Smiley, S T; Boyer, S N; Heeb, M J et al. (1997) Protein S is inducible by interleukin 4 in T cells and inhibits lymphoid cell procoagulant activity. Proc Natl Acad Sci U S A 94:11484-9
Smiley, S T; Grusby, M J (1997) Dual-receptor T cells expressing one self-restricted TCR. Scand J Immunol 45:726-30
Kaplan, M H; Boyer, S N; Grusby, M J (1996) Genomic organization of the murine CTL lipase gene. Genomics 35:606-9