Novel Cytokines From Activated Macrophages

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Abstract

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 CXCL9/Mig and mouse CXCL10/Crg-2/IP-10, previously un-described 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, which they share with CXCL11/I-TAC, another interferon-inducible chemokine. Work in the last year has focused on understanding the roles of CXCR3 as well as other chemokine receptors on subsets of human lymphocytes. We found that among the chemokine receptors expressed on human effector/memory CD4 T cells, CXCR3 is unusual in being induced early after T cell activation and that in addition to roles in inflammation in peripheral tissues CXCR3 is likely to function in organizing responses within lymphoid organs. Using data for CXCR3 and CCR5, two receptors associated with Th1 responses, we have been developing a model describing the sequential induction of chemokine receptors along the pathway of T cell activation and differentiation. This model is in turn allowing us to make and test predictions about the functions of novel CD 4 T cell subsets identified by their chemokine receptor expression. In addition, we have been investigating possible roles for Crg-2/IP-10 and I-TAC in HIV/AIDS, related to the co-expression of CXCR3 and the major HIV co-receptor, CCR5, on CD4+ memory T cells. Our findings suggest that the recruitment of CCR5+ memory/effector T cells by CXCR3 ligands may contribute to the dissemination of HIV infection. Our studies have used human cells and human tissues studied by flow cytometry with cell sorting, immunohistochemistry, in situ hybridization, polymerase chain reaction, ELISA, and assays for receptor function including cell migration and actin polymerization.