The purpose of this project is to continue studies on the function of the Ly-6A/E alloantigens in the immune system at both the cellular and molecular levels in four major areas of investigation. First, the possibility that Ly-6A/E marks a specific lineage of T cells will be examined by experiments which characterize the phenotype of mature T cells which develop from Ly-6A/E+ and Ly-6A/E- precursor cells and in studies which examine the function of Ly-6A/E+ and Ly-6A/E- CD4 and CD8 mature T cells. A second group of studies will explore the molecular basis by which an anti-Ly-6A/E mAb blocks IL-2 production of T cell hybridomas and normal T cells stimulated through the CD3/TcR complex. In part, these studies will focus on changes in expression of individual CD3 components or in patterns of phosphorylation of CD3 subunits for cells activated through Ly-6A/E. The possibility that the Ly-6 pathway may regulate IL-2 at transcriptional or posttranscriptional levels will also be determined. This group of experiments will also test the basis for the apparent IL-2 independent proliferation of alloantigen-stimulated T cells when cultured in the presence of an anti-Ly-6A/E mAb. Third, the modulation of B cell function will be further characterized by examining whether immunoglobulin isotype expression is altered after stimulation of B cells through Ly-6 molecules. Binding studies to Ly-6A/E will be performed with cells transfected with Ly-6A/E cDNA or purified Ly-6A/E protein in attempts to identify the physiological ligand for Ly-6A/E. These studies should extend our knowledge of the role of Ly-6 molecules in immune responses and may be relevant to cancer and autoimmunity since Ly-6 proteins are abnormally expressed or regulated in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA046096-04
Application #
3189372
Study Section
Experimental Immunology Study Section (EI)
Project Start
1987-09-01
Project End
1995-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
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Malek, T R; Fleming, T J; Codias, E K (1994) Regulation of T lymphocyte function by glycosylphosphatidylinositol (GPI)-anchored proteins. Semin Immunol 6:105-13
Fleming, T J; Malek, T R (1994) Multiple glycosylphosphatidylinositol-anchored Ly-6 molecules and transmembrane Ly-6E mediate inhibition of IL-2 production. J Immunol 153:1955-62
Ivanov, V; Fleming, T J; Malek, T R (1994) Regulation of nuclear factor-kappa B and activator protein-1 activities after stimulation of T cells via glycosylphosphatidylinositol-anchored Ly-6A/E. J Immunol 153:2394-406
Fleming, T J; O'hUigin, C; Malek, T R (1993) Characterization of two novel Ly-6 genes. Protein sequence and potential structural similarity to alpha-bungarotoxin and other neurotoxins. J Immunol 150:5379-90
Codias, E K; Malek, T R (1993) Subsets of activated CD4 T lymphocytes refractory for secretion of IL-2 are distinguished by expression of Ly-6A/E in BALB/c mice. J Immunol 151:5918-29
Fleming, T J; Fleming, M L; Malek, T R (1993) Selective expression of Ly-6G on myeloid lineage cells in mouse bone marrow. RB6-8C5 mAb to granulocyte-differentiation antigen (Gr-1) detects members of the Ly-6 family. J Immunol 151:2399-408
Codias, E K; Fleming, T J; Zacharchuk, C M et al. (1992) Role of Ly-6A/E and T cell receptor-zeta for IL-2 production. Phosphatidylinositol-anchored Ly-6A/E antagonizes T cell receptor-mediated IL-2 production by a zeta-independent pathway. J Immunol 149:1825-52
Cray, C; Keane, R W; Malek, T R et al. (1990) Regulation and selective expression of Ly-6A/E, a lymphocyte activation molecule, in the central nervous system. Brain Res Mol Brain Res 8:9-15
Codias, E K; Rutter, J E; Fleming, T J et al. (1990) Down-regulation of IL-2 production by activation of T cells through Ly-6A/E. J Immunol 145:1407-14

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