During the last year, the project has focused on chemokine receptor signal transduction in human memory T cells. One purpose of this project has been to understand chemokine receptor functioning in memory T cells, since these are the cells that can migrate into tissues to provide protection against infection or to cause damage in autoimmune and/or inflammatory disease and chemokine receptors help to control this migration. Naive T cells, which are cells that have not been activated by their cognate antigen, and which do not migrate into non-lymphoid tissue, express only two chemokine receptors, whereas memory cells express at least fifteen different species of chemokine receptors in various combinations. We hypothesized that this increase in the complexity of chemokine receptor expression on memory T cells might be associated with changes in the types of proteins within the cell that transmit the signals from the chemokine receptors that ultimately affect cell trafficking. Within the cell, chemokine receptors interact with G proteins, particularly G proteins of the Gi/o subfamily, of which there are four members that are commonly expressed. These proteins are named for their alpha subunits alphas 1,2,3, and O. The major alpha subunits previously known to be expressed in leukocytes, including T cells, were Galpha2 and Galpha3. We found that memory T cells also express GalphaO. By knocking down gene expression using siRNAs, we found that although GalphaO remains at relatively low levels in these cells, GalphaO proteins transmit signals from chemokine receptors to a degree comparable to proteins containing the other Galpha subunits. Moreover, we discovered that nave (but not memory) T cells express Galpha1, and that this protein can also contribute to chemokine receptor signaling in these cells. Together, our data demonstrate differences in downstream mediators of chemokine receptor signaling that depend on the states of T cell differentiation, and establish that Galpha subunits of apparently low abundance can nonetheless make important contributions to receptor signaling.
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