Regulation of CXCR4 expression in human T lymphocytes by calcium and calcineurin

Principally expressed on the surface of T lymphocytes, the chemokine and HIV receptor CXCR4 has been shown to serve key roles in both chemotaxis and HIV-1-entry into T cells. Understanding the regulation of CXCR4 expression is therefore of paramount importance to further elucidating its endogenous role and contributions to HIV-1 pathogenesis. Using an RNase protection assay (RPA), we have demonstrated that mitogenic stimulation of purified human peripheral blood T lymphocytes (PBL) decreased CXCR4 mRNA relative to unstimulated controls in a calcineurin-dependent manner; an expression pattern mimicked by the chemokine receptor CCR7. A change in transcriptional activity, not in mRNA stability, was required for control of CXCR4 and CCR7 expression. Changes in CXCR4 mRNA expression translated into a stimulation- and calcineurin-dependent decrease in cell surface CXCR4 expression. We have previously demonstrated that CXCR4 mRNA and protein is regulated by cAMP; here we show that calcium and calcineurin signaling pathways modify cAMP-driven changes. Moreover, we provide data supporting a role for the transcription factor YY1 in calcineurin-dependent regulation of CXCR4 expression.