Migration of Vδ1 and Vδ2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1–infected patients: competition by HIV-1 Tat

Abstract

We show that HIV-1-infected patients have increased concentrations of circulating V␦1 T cells (2.2%-9.0% of T lymphocytes; healthy donors, 1.0%-2%) and, in some instances, V␦2 T cells (3.5%-4.8% vs 2.0%-3.3%). In these patients, both V␦1 and V␦2 T cells are CXCR3 ؉ CXCR4 ؉ , whereas in healthy donors CXCR4 was preferentially expressed on V␦1 T lymphocytes. ␥␦ T cells transmigrated across endothelial monolayers, in response to interferon-␥-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␦1 CXCR3 ؉ cells, whereas V␦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.

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

“…Of note, human gd T cells express other chemokine receptors like CCR5 and CXCR3, and have been shown to also migrate in vitro toward CCL3, CCL4, CCL5, CXL10, CXCL11, and CXCL12 (25)(26)(27)(28). Thus, it will be worthwhile to assess the relative contributions of these pathways, in addition to CCR2/CCL2, to tumor infiltration by gd T cells, particularly Vd1 PBLs.…”

“…Human gd T cells have been shown to migrate in vitro toward CCL2, CCL3, CCL4, CCL5, CXL10, CXCL11, and CXCL12 (25)(26)(27)(28). In vivo studies with mice have further allowed dissection of the role of homeostatic or inflammatory chemokines, depending on whether they direct gd T cell migration in the absence or presence of inflammatory stimuli.…”

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

“…Also in some human cells, CCL21 is a functional ligand for endogenously expressed CXCR3 (Dijkstra et al, 2004;Poggi et al, 2004). To investigate whether CXCR3 can transduce the ligand signals in colon cancer cells, we first performed calcium mobilization assays.…”

Soluble HIV Tat Protein Removes the IL-7 Receptor α-Chain from the Surface of Resting CD8 T Cells and Targets It for Degradation

“…We have recently shown this downregulation of CD127 on the surface of CD8 T cells is mediated at least in part by soluble HIV Tat protein (31). Tat, a 15-kDa viral protein, is secreted by HIV-infected cells and can be found in the media during in vitro infection (32,33) as well as in the serum of HIV-infected patients (34). Acting in a paracrine fashion, secreted Tat protein is rapidly internalized by neighboring uninfected cells (33,35,36) and localizes to both the nucleus and the cytoplasm (33,37).…”