Abstract:
We have studied three molecules found on the surface of cells in the human immune system. CD4, Leu-8/TQ1 and CD27 are glycoproteins found on T lymphocytes, the cells which in large part regulate the body's immune defenses. Each of these molecules participates in a different aspect of T cell function. CD4 is part of the receptor which allows recognition of invading organisms. Leu-8/TQ1 allows lymphocytes to leave the vascular system to interact with pathogens concentrated in lymph nodes, and CD27 may help T cells proliferate as a response to antigen recognition. CD4 is also the principal receptor for HIV, the virus which causes AIDS. HIV kills T cells and destroys the immune defenses against invasion by pathogens. We have studied the CD4 sequence requirements for one aspect of this process, the HIV mediated formation of necrotic multinucleated cells called syncytia. Unlike humans, chimpanzees show no symptoms of AIDS when infected with HIV. We have shown that chimpanzee and rhesus monkey lymphocytes do not form syncytia with HIV infected cells in vitro, as human lymphocytes do. By isolating cDNA clones encoding these non-human primate CD4 molecules we have shown that this resistance to syncytium formation resides in the CD4 receptor. By in vitro mutagenesis we have located a single amino acid difference between human and chimp CD4 glycoproteins which confers susceptibility or resistance to HIV mediated syncytium formation. Sequence analysis of cDNA clones encoding the pan-leukocyte antigen Leu-8/TQ1 revealed a peripheral lymph node homing receptor, homologous to the mouse Mel-14 antigen. This protein permits lymphocyte adhesion to, and migration through lymph node endothelium allowing T cells to respond to foreign antigens concentrated in lymph nodes. Two forms of Leu-8/TQ1, differing in their mode of attachment to the cell, were found. Active shedding of this receptor in response to antigen was seen, confirming the relationship between tissue localization and lymphocyte function. CD27 may play a role in the proliferative response of lymphocytes subsequent to their encounter with antigen. Its structure, predicted from a cDNA we cloned and sequenced, is similar to CD40 and the nerve growth factor receptor. Previous studies show that CD27 surface expression increases when cells are stimulated and that perturbation of this receptor can induce increased proliferation. Together these data suggest that CD27 may be a T cell growth factor receptor. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD90-21786)
Keywords: Animal Antigens, CD4/*GENETICS/IMMUNOLOGY Antigens, Differentiation/*GENETICS/IMMUNOLOGY Antigens, Differentiation, T-Lymphocyte/*GENETICS/IMMUNOLOGY Cell Adhesion Molecules/GENETICS/IMMUNOLOGY Cells, Cultured Chimpansee troglodytes Human HIV/PHYSIOLOGY Membrane Glycoproteins/*GENETICS/IMMUNOLOGY Receptors, Immunologic/GENETICS/IMMUNOLOGY T-Lymphocytes/*IMMUNOLOGY/MICROBIOLOGY THESIS 901230
M90C3719
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