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.
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.
Poggi
Alessandro
A
Laboratory of Immunology, National Institute fo Cancer Research, Largo R. Benzi 10, I-16132, Genoa, Italy. poggi@vega.cba.unige.it
Carosio
Roberta
R
Fenoglio
Daniela
D
Brenci
Sabrina
S
Murdaca
Giuseppe
G
Setti
Maurizio
M
Indiveri
Francesco
F
Scabini
Silvia
S
Ferrero
Elisabetta
E
Zocchi
Maria Raffaella
MR
D000328:Adult; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D015696:Gene Products, tat / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D014471:Umbilical Veins / Q000166:cytology; D054322:tat Gene Products, Human Immunodeficiency Virus
C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015696:Gene Products, tat; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D054322:tat Gene Products, Human Immunodeficiency Virus; D019869:Phosphatidylinositol 3-Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases