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Engagement of CD28 Modulates CXC Chemokine Receptor 4 Surface Expression in Both Resting and CD3-Stimulated CD4⁺ T Cells¹

Paola Secchiero^2,3,*,, Davide Zella^2,*, Sabrina Curreli^*, Prisco Mirandola^*,, Silvano Capitani, Robert C. Gallo^* and Giorgio Zauli

^* Institute of Human Virology, University of Maryland, Baltimore, MD 21201; Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy; and Institute of Normal Human Morphology, G. D’Annunzio University of Chieti, Chieti Scalo, Chieti, Italy

Optimal CD4⁺ T cell activation requires the cooperation of multiple signaling 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, stimulated with anti-CD3 and anti-CD28 mAbs, immobilized on plastic. Anti-CD3 alone induced a progressive down-regulation of surface CXCR4, accompanied by a significant decline in the entry of the HXB2 T cell line-tropic (X4-tropic) HIV-1 clone in CD4⁺ T cells. Of note, this effect was strictly dependent 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 synergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4⁺ T cells. On the other hand, anti-CD28 counteracted the CXCR4 down-modulation induced by anti-CD3. The latter effect was particularly evident when anti-CD28 was associated to suboptimal concentrations of anti-CD3. Because CXCR4 is the major coreceptor for the highly cytopathic X4-tropic HIV-1 strains, which preferentially replicate 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 cells provides one relevant mechanism for the progression of HIV-1 disease.

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