TNF-α-induced secretion of C-C chemokines modulates C-C chemokine receptor 5 expression on peripheral blood lymphocytes

Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO(+) memory subset. In this study, we report that TNF-alpha delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level, Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1 beta stimulation. The effect is mediated via the p80 type IT TNF receptor (TNFR2), which induces NF-KB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and RANTES. Expression of these chemokines directly down-regulates CCR5, These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains.