Engagement of CD28 modulates CXC chemokine receptor 4 surface expression in both resting and CD3-stimulated CD4(+) T cells

Optimal CD4(+) T cell activation requires the cooperation of multiple signa ling pathways coupled to the TCR-CD3 complex and to the CD28 costimulatory molecule. In this study, we have investigated the expression of surface CXC chemokine receptor 4 (CXCR4) in enriched populations of CD4(+) T PBL, stim ulated with anti-CD3 and anti-CD28 mAbs, immobilized on plastic. Anti-CD3 a lone induced a progressive down-regulation of surface CXCR4 accompanied by a significant decline in the entry of the HXB2 T cell line-tropic (X4-tropi c) HIV-1 clone in CD4(+) T cells, Of note, this effect was strictly depende nt on the presence in culture of CD14(+) monocytes, On the other hand, anti -CD28 alone induced a small but reproducible increase in the expression of surface CXCR4 as well as in the entry of HXB2 HIV-1 clone in resting CD4(+) T cells. When the two mAbs were used in combination, anti-CD28 potently sy nergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4(+) T cells. On the other hand, an ti-CD28 counteracted the CXCR4 down-modulation induced by anti-CD3, The lat ter effect was particularly evident when anti-CD28 was associated to subopt imal concentrations of anti-CD3, Because CXCR4 is the major coreceptor for the highly cytopathic X4-tropic HIV-1 strains, which preferentially replica te in proliferating CD4(+) T cells, the ability of anti-CD28 to up-regulate the surface expression of CXCR4 in both resting and activated CD4(+) T cel ls provides one relevant mechanism for the progression of HIV-1 disease.