Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-γ, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-β (β isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.

In the present study, we demonstrated that opsonization of primary HIV-1 with human complement enhances infection of immature monocyte-derived dendritic cells (iDC) and transmission in trans of HIV to autologous CD4⁺ T lymphocytes. Infection of iDC by opsonized primary R5- and X4-tropic HIV was increased 3- to 5-fold as compared with infection by the corresponding unopsonized HIV. Enhancement of infection was dependent on CR3 as demonstrated by inhibition induced by blocking Abs. The interaction of HIV with CCR5 and CXCR4 on iDC was affected by opsonization. Indeed, stromal-derived factor-1 was more efficient in inhibiting infection of iDC with opsonized R5-tropic HIV-1_BaL (45%) than with heat-inactivated complement opsonized virus and similarly RANTES inhibited more efficiently infection of iDC with opsonized X4-tropic HIV-1_NDK (42%) than with heat-inactivated complement opsonized virus. We also showed that attachment of complement-opsonized virus to DC-specific ICAM-grabbing nonintegrin (DC-SIGN) molecule on iDC and HeLa DC-SIGN⁺ CR3⁻ cells was 46% and 50% higher compared with heat-inactivated complement opsonized virus, respectively. Hence, Abs to DC-SIGN suppressed up to 80% and 60% the binding of opsonized virus to HeLa cells and iDC, respectively. Furthermore, Abs to DC-SIGN inhibited up to 70% of the infection of iDC and up to 65% of infection in trans of autologous lymphocytes with opsonized virus. These results further demonstrated the role of DC-SIGN in complement opsonized virus uptake and infection. Thus, the virus uses complement to its advantage to facilitate early steps leading to infection following mucosal transmission of HIV.

Signaling lymphocytic activation molecules Slam and cancers: friends or foes? Signaling lymphocytic activation molecules Slam and cancers: friends or foes?

Summary: The present study demonstrates that human breast milk and normal human polyclonal immunoglobulins purified from plasma [intravenous immunoglobulins (IVIg)] contain functional natural immunoglobulin A (IgA) and IgG antibodies directed against the carbohydrate recognition domain (CRD) domain of the dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin (DC‐SIGN) molecule, which is involved in the binding of human immunodeficiency virus (HIV)‐1 to dendritic cells (DCs). Antibodies to DC‐SIGN CRD were affinity‐purified on a matrix to which a synthetic peptide corresponding to the N‐terminal CRD domain (amino‐acid 342–amino‐acid 371) had been coupled. The affinity‐purified antibodies bound to the DC‐SIGN peptide and to the native DC‐SIGN molecule expressed by HeLa DC‐SIGN⁺ cells and immature monocyte‐derived dendritic cells (iMDDCs), in a specific and dose‐dependent manner. At an optimal dose of 200 µg/ml, natural antibodies to DC‐SIGN CRD peptide purified from breast milk and IVIg stained 25 and 20% of HeLa DC‐SIGN⁺ cells and 32 and 12% of iMDDCs, respectively. Anti‐DC‐SIGN CRD peptide antibodies inhibited the attachment of virus to HeLa DC‐SIGN by up to 78% and the attachment to iMDDCs by only 20%. Both breast milk‐ and IVIg‐derived natural antibodies to the CRD peptide inhibited 60% of the transmission in trans of HIV‐1_JRCSF, an R5‐tropic strain, from iMDDCs to CD4⁺ T lymphocytes. Taken together, these observations suggest that the attachment of HIV to DCs and transmission in trans to autologous CD4⁺ T lymphocytes occur through two independent mechanisms. Our data support a role of natural antibodies to DC‐SIGN in the modulation of postnatal HIV transmission through breast‐feeding and in the natural host defence against HIV‐1 in infected individuals.