The overall goal of the project has been to identify and characterize the function of macrophage products of potential importance in immune and inflammatory responses in order to manipulate these responses for clinical benefit. This laboratory identified mouse and human Mig and mouse Crg-2/IP-10, previously undescribed members of a family of small secreted proteins, termed chemokines. Mig and Crg-2/IP-10 are inducible in macrophage and other cells by IFN-gamma and target activated T cells, B cells and NK cells through the CXCR3 receptor. Work in the last year has focused on CXCR3, which has been reported to be expressed selectively on T helper 1 (Th1) CD4 cell lines. We showed that CXCR3 is induced on naive CD4 T cells early after activation independent of the cytokine environment, but that expression on Th1 cells remains, even after the cells come to rest, while persistent expression on Th2 cells requires continued or repeated activation. We have shown that early induction of CXCR3 expression after CD4 T cell activation occurs in vivo on recently-activated tonsillar cells and that ligands for CXCR3 are expressed by tonsillar dendritic cells. Together, these data suggest that CXCR3 may be important for trafficking of CD4 T cells soon after activation both within lymphoid organs and to peripheral sites of infection/inflammation. Recently, chemokines and their receptors have been found to be of central importance in HIV disease, since some chemokine receptors are used by HIV to enter cells. In one part of this project, we have refined a flow cytometric assay for calcium fluxes to analyze lymphocytes for signalling through chemokine receptors both by natural ligands and by HIV envelope glycoproteins (Envs). Collaborative work with the Laboratory of Immunoregulation has shown that the ability of HIV strains to infect macrophages correlates with the abilities of Envs from these strains to signal through CCR5, which may form part of the basis for the macrophage tropism of these strains. Finally, we have begun to investigate a possible role for CXCR3 in AIDS pathogenesis, since virtually all CD4 memory T cells that express the major HIV coreceptor, CCR5, co-express CXCR3.
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