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Finally, CD4+T cells from those lines that expressed intermediate levels of hSLAM, i.e., FVB/N (F-4), C57BL/6 (B-2), and FVB/N C57BL/6 (FB-8), showed less infectivity by MV than CD4+T cells from lines F-2, FB-25, and FB-30 but more than lines FB-12, FB-37, and FB-39. receptor hSLAM and inhibited cell division and proliferation of hSLAM+but not hSLAMT cells. Therefore, these tg mice provide the opportunity for analyzing and comparing MV-T cell interactions and MV pathogenesis in cells expressing only the hSLAM MV receptor with those of tg mice whose T cells selectively express another MV receptor, CD46. Since measles virus (MV) was isolated and attenuated to produce a successful vaccine (7,20), it was Firategrast (SB 683699) shown to cause a progressive central nervous system (CNS) disease (subacute sclerosing panencephalitis) and was found to be capable of suppressing immune responses (28,53). Firategrast (SB 683699) More recently, two developments have aroused interest in the nature of MV. The first was the discovery of two cell surface receptors for MV, namely, the CD46 molecule, which is a member of the complement regulatory cascade of proteins (6,26,33), and signaling lymphocytic activation molecule (SLAM), a T-cell costimulatory molecule (9,18,52). Whereas the CD46 molecule is ubiquitously expressed on all nucleated cells, SLAM is expressed only on immature thymocytes, activated and memory T cells, B cells, and activated monocytes and dendritic cells (4,29,30,40,49). The second development was a better understanding of mechanisms of MV-induced immunosuppression. Although the route of infection by MV is respiratory, and despite its widespread dissemination to the skin, the intestinal tract, and the nervous system, the virus has a strong predilection for lymphoid tissues in the early as well as late stages of the disease. Furthermore, lymphoid tissues and cells provide not only a replication site but also a means of transporting the virus within the body. Since both CD46, constitutively, and SLAM, inducibly, are concomitantly present on cells of the human immune system, the relative individual contribution of Firategrast (SB 683699) either of the two MV receptors in MV-induced immunosuppression has been difficult to sort out. MV has been known to induce mitogen unresponsiveness of T cells by direct infection and contact with infected cells (12,43,56). However, the lack of a suitable small-animal model has impeded progress toward understanding the pathogenic effects Firategrast (SB 683699) of MV, especially its ability to induce immunosuppression, a CNS disease, and virus-immune cell and virus-neuron interactions. Following the identification of MV receptor CD46, investigators in several laboratories have attempted to express human CD46 in transgenic (tg) mice as models that could be infected by MV (16,36,41,57). The human CD46 protein has a 45% homology with mouse CD46 (54). Mice are not infected by MV unless the virus has been adapted to the murine cells by multiple passages (24) or unless human CD46 is expressed in the mouse. In terms of understanding and solving the puzzle of how MV suppresses the immune responses, recent studies have suggested that MV infects and alters functions of T cells (11,32,34) and antigen-presenting cells (APC) (14,45,46) and that infection skews the T-cell response to a Th2 phenotype (13). SLAM is a glycoprotein ligand found on the surface of immature thymocytes, activated and memory T cells, B cells, and activated APC (4,29,30,40,49). Sequence analyses and gene mapping place SLAM in the CD2 immunoglobulin (Ig) superfamily along with related genes, such as those for 2B4 and SF 2001 (5,10). SLAM and SLAM-related cell surface receptors are thought to play an important role in adhesion and signaling at the immune synapse between the APC Rabbit Polyclonal to ACTL6A and the T cell. The homology between human and murine Firategrast (SB 683699) SLAM is 58%, and while human SLAM (hSLAM) serves as a receptor for MV, murine SLAM does not (38). Owing to its expression on cells of the immune system and its role.