Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are mediators of cellular proliferation and functions, which are produced by platelets, thymic epithelial cells, macrophages and other phagocytes. Endothelial differentiation genes encode a subfamily of G protein-coupled receptors (GPCRs), termed Edg Rs, of which Edg-l, -3, -5, and -8 Rs are specific for S1P and Edg-2, -4, and -7 Rs for LPA. Thymocytes and T cells express high levels of Edg Rs in distinctive patterns. The predominant Edg Rs expressed are: 3 and 5 for S1P by thymocytes, 4 by CD4+ T cells constitutively, 2 and 4 for LPA by activated CD4+ T cells, and only traces of 2 and 5, but not 4, by CD8+ T cells before and after activation. The central working hypothesis is that CD4+ cells recognize and respond to LPA differently in two specific states of Edg R expression: prior to activation Edg-4 Rs dominate and mediate adhesion and migration, but suppress proliferation and IL-2 generation, whereas after activation Edg-2 Rs dominate and mediate proliferation and cytokine generation, but inhibit migration.
The specific aims are: 1. Edg Rs will be delineated in mouse and human T cell subsets, B cells and macrophages using newly developed panels of mouse and rat monoclonal anti-Edg R antibodies. 2. Determinants of developmental and constitutive expression of Edg-4 Rs by CD4+ T cells will be defined and mechanisms of Edg-4 R signaling and effects elucidated in CD4+ T cells and Th1 and Th2 subsets. 3. Mechanisms of cytokine-mediated upregulation of Edg-2 Rs in CD4+ T cells will be delineated and pathways of Edg-2 R signaling and effects characterized in CD4+ T cells and Th1 and Th2 subsets. 4. Signaling and functional interactions among Edg-2, -3 and -4 Rs will be analyzed in Jurkat T cell transfectants. 5. Edg R transduction of T cell protection from apoptosis will be studied to characterize the distinctive mechanisms of LPA and SIP suppression of Bax and inhibition of caspases. A greater knowledge of Edg R expression and functions in T cells will reveal specific mechanisms of lysolipid phosphate immunoregulation and identify new targets for correcting immune disorders.
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