In 1998, we made a number of findings in our studies of the regulation of dendritic cells (DCs) and immunodeficiency viruses. Most of our results in this area are still in the form of manuscripts under review. First, we completed our study of how best to prepare DCs from macaque bone marrow. These DCs are phenotypically very similar to human DCs and can be infected with HIV-2. Second, we compared how CD40 ligation regulates two key antigen presenting cells, B cells and DCs. CD40 ligation induces the expression of a set of cytokines in DCs but not in B cells; furthermore, even though expression of the survival protein cIAP2 is induced via CD40 in both cell types, the induction pathway leading to cIAP2 expression is different in DCs vs. B cells. Third, we found that resting CD4+ T cells must first express the c-myc protooncogene in order to express HIV-1. Antisense c-myc oligonucleotides specifically block the import of HIV-1 to the nucleus in activated CD4+ T cells. The antisense oligos apparently have this effect by inducing a truncated dominant negative form of c-myc protein. Fourth, we assisted in the characterization of a novel macaque herpesvirus isolated from one of the animals in our immunogenetics colony that developed mycosis fungoides. Fifth, we compared the signaling requirements of naive vs. memory CD4+ T cells, since HIV-1 is expressed particularly in CD4+ T cells. A cyclic AMP-specific phosphodiesterase, PDE7, is required for memory T cells to proliferate and thus, regulating this enzyme may be one means by which HIV-1 might be regulated. In other projects, we characterized the signal transduction pathway mediated by CDw150, which may play a key role in X-linked lymphoproliferative disease. We published several studies on the regulation of B lymphocyte fate, a novel follicular dendritic cell (FDC)-associated receptor, FDCR1, and on kinase regulation of B cell signaling pathways, and prepared a comprehensive review of this area. FUNDING NIH grants RR00166, GM379005, GM42508, and DE08229. Graves, J.D., Gotoh, Y., Draves, K.E., Ambrose, D., Han, D., Wright, M., Chernoff, J., Clark, E.A. and Krebs, E.G. Caspase-mediate activation and induction of apoptosis by the mammalian Ste-20-like kinase Mst1. EMBO J. 17 2224-2234, 1998. Cornall, R.J., Cyster, J.G., Hibbs, M.L., Dunn, A.R., Otipoby, K.L., Clark, E.A., and Goodnow, C.C. Polygenic regulation of complex traits in autoimmunity Lyn kinase, CD22 and SHP-1 phosphatase are limiting elements of a biochemical pathway that regulates BCR signaling and selection. Immunity 8 497-508, 1998. Graves, J.D., Draves, K.E., Craxton, A., Krebs, E.G., and Clark, E.A. A comparison of signaling requirements for apoptosis of human B lymphocytes induced by the B cell receptor and CD95/Fas. J. Immunol. 161 168-174, 1998. Yun, T., Chaudhary, P., Shu, G.L., Frazer, J.K., Ewings, M.K., Schwartz, S.M., Pascual, V., Hood, L.E., and Clark, E.A. OPG/FDCR1, a TNFR family member, is expressed in lymphoid cells and is upregulated by ligating CD40. J. Immunol. 161 6113-6121, 1998. Craxton, A., Shu, G., Graves, J. D., Saklatvala, J., Krebs, E.G., and Clark, E. A. p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J. Immunol. 161 3225-3236, 1998. Jiang, A., Craxton, A., Kurosaki, T., and Clark, E.A. Different protein tyrosine kinases are required for B cell antigen receptor-mediated activation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase. J. Exp. Med. 188 1297-1306, 1998. Hashimoto, A., Okada, H., Jiang, A., Kurosaki, M., Greenberg, S., Clark, E.A., and Kurosaki, T. Involvement of GTPases and Phospholipase C-_2 in extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase activation by the B cell antigen receptor. J. Exp. Med. 188 1287-1295, 1998.
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