The aim of this project is to define the molecular mechanisms by which blood leukocytes migrate to specific tissue sites that are inflamed or infected. We have focused on chemoattractant proteins that mediate this process and have identified members of a large family of chemoattractant receptors that are deployed on the leukocyte cell surface. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, including herpesviruses, poxviruses and HIV. We use genomics, molecular biology, cell biology and epidemiology, and collaborations with virologists, as the principle methods for analyzing these molecules. A major question addressed in previous years and continued in FY2003 is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. In this regard, we have found that CX3CR1-M280, an inactive variant of the chemokine receptor CX3CR1, is highly associated with decreased risk of atherosclerosis. This result was obtained through study of the Framingham Heart Study, the gold standard patient cohort for delineating risk factors for cardiovascular disease. Moreover, the result was confirmed in a CX3CR1 knockout mouse created in the lab, which was found to have a markedly reduced risk of atherosclerosis. This suggests that CX3CR1 may be a suitable target for drug development in atherosclerosis. Because the CX3CR1 knockout allele and CX3CR1-M280 are both associated with reduced risk of atherosclerosis even in heterozygotes, we have hypothesized that CX3CR1 receptor expression may be limiting and that its regulation may be important for understanding atherosclerosis and other inflammatory disease processes. In this regard we have examined the effect of IL-15 on CX3CR1 expression in NK cells, since these cells express high levels of the receptor and are dependent on IL-15 function. Unexpectedly we found that IL-15 is a potent negative regulator of CX3CR1 expression on NK cells in a mouse model, both in vitro and in vivo. Also unexpectedly, IL-2 has the opposite effect. These results suggest that the gamma-c cytokines IL-2 and IL-15, which signal through the same receptor chains, must use differential signaling pathways to affect CX3CR1 expression and that IL-15 expansion of NK cells may cripple the cells with regard to CX3CR1-mediated trafficking in cell therapy applications.
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