Cytokines and cell surface molecules independently induce CXCR4 expressionon CD4(+) CCR7(+) human memory T cells

In the present study, we show that IL-2, IL-4, IL-7, and IL-15 are able to induce functional CXCR4 surface expression on resting in vitro-generated CD 4(+) CXCR4(-) CCR7(+) memory T cells. Cytokine-mediated induction of CXCR4 expression was associated with an increase in CXCR4 transcription, enhanced stromal-derived factor-1-induced T cell migration in vitro, and increased susceptibility of these cells to infection with X4 strains of HIV-1, CXCR4 expression could also be induced through an alternative pathway, following coculture of these cells with CD40-activated, autologous, CD34(+) progenito r-derived dendritic cells. Although these dendritic cells express transcrip ts for IL-7 and IL-15, addition of neutralizing anti-IL-7R and IL-15 mAbs d id not block induction of CXCR4 expression. Indeed, dendritic cell-mediated up-regulation of CXCR4 expression was found to depend on CD40/CD154 and CD 134/CD134L interactions. Whereas activated autologous dendritic cells induc ed the expression of both CXCR4 and CD25 on a portion of CCR7(+) memory T c ells, concomitant CD3-mediated activation of these cells further enhanced C D25 expression, but, in contrast, prevented induction of CXCR4 expression. This observation suggests that triggering of the CD134 and CD154 molecules, in contrast to TCR/CD3 complex-mediated stimulation, results in simultaneo us T cell activation and CXCR4 expression. Taken together, these results sh ow that common gamma-chain-interacting cytokines as well as signals mediate d via noncognate interactions between activated dendritic cells and memory T cells are involved in the up-regulation of CXCR4 expression.