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 undescribed members of a family of small secreted proteins, termed chemokines. CXCL9 and CXCL10 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 another chemokine receptor, CCR4, on subsets of human lymphocytes. CXCR3 is found preferentially on T helper 1 cells and CCR4, the receptor for chemokines CCL17 and CCL22, is found preferentially on T helper 2 cells. We found that CXCR3 and CCR4 are expressed on a subsets of CD4+ (helper) T cells that are so early on the pathway of differentiation that they display no other markers typically ascribed to memory/effector T cells. These CXCR3+ and CCR4+ early memory cells were able to produce cytokines typical of T helper 1 and T helper 2 cells, respectively. These data have implications for the pathways through which helper T cells are activated and differentiate to produce memory cells, which is important for protection against infection and effective vaccination. In addition, we have investigated roles for the chemokines CXCL10 and CXCL11 in HIV/AIDS, related to the co-expression of CXCR3 and the major HIV coreceptor, CCR5, on CD4+ memory T cells. Our findings suggest that the recruitment of CCR5+ memory/effector T cells by CXCR3 ligands to other infected cells and to lymph nodes 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.
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