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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2205-2213.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-08-2928.


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IMMUNOBIOLOGY

Migration of V{delta}1 and V{delta}2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1–infected patients: competition by HIV-1 Tat

Alessandro Poggi, Roberta Carosio, Daniela Fenoglio, Sabrina Brenci, Giuseppe Murdaca, Maurizio Setti, Francesco Indiveri, Silvia Scabini, Elisabetta Ferrero, and Maria Raffaella Zocchi

From the Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy; CEBR and Department of Internal Medicine, DIMI, University of Genoa, Italy; and Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Milan, Italy.

We show that HIV-1–infected patients have increased concentrations of circulating V{delta}1 T cells (2.2%-9.0% of T lymphocytes; healthy donors, 1.0%-2%) and, in some instances, V{delta}2 T cells (3.5%-4.8% vs 2.0%-3.3%). In these patients, both V{delta}1 and V{delta}2 T cells are CXCR3+CXCR4+, whereas in healthy donors CXCR4 was preferentially expressed on V{delta}1 T lymphocytes. {gamma}{delta} T cells transmigrated across endothelial monolayers, in response to interferon-{gamma}–inducing protein-10 (IP-10/CXCL10), stromal cell–derived factor-1 (SDF-1/CXCL12), or both, according to the expression of the specific receptors CXCR3 and CXCR4. Interestingly, 6Ckine/SLC/CCL21 was more effective than IP-10/CXCL10 on V{delta}1 CXCR3+ cells, whereas V{delta}2 CXCR3+ cells were driven more efficiently by IP-10/CXCL10. IP-10/CXCL10– and SDF-1/CXCL12–induced transmigration was dependent on phosphoinositide-3 kinase (PI-3K), as demonstrated by the use of the specific blockers wortmannin and LY294002 and by the activation of the downstream serine kinase Akt/PKB on ligation of CXCR3 and CXCR4. Occupancy of CXCR3, but not of CXCR4, led to CAMKII activation; accordingly, the CAMKII inhibitors KN62 and KN93 decreased IP-10/CXCL10– but not SDF-1/CXCL12–driven transmigration. Finally, HIV-1 Tat, which is present in the serum of HIV-1–infected patients, interferes with the chemotactic activity of these chemokines because of the cysteine-rich domain of the protein, which contains CXC and CC chemokine–like sequences.


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