title: Soluble HLA-G dampens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56bright and CD56dim NK cells.
abstract: Soluble HLA-G (sHLA-G) inhibits natural killer (NK) cell functions. Here, we investigated sHLA-G-mediated modulation of (1) chemokine receptor and NK receptor expression and function and (2) cytokine and chemokine secretion in CD56bright and CD56dim NK cells. sHLA-G-treated or untreated peripheral blood (PB) and tonsil NK cells were analyzed for chemokine receptor and NK receptor expression by flow cytometry. sHLA-G down-modulated (1) CXCR3 on PB and tonsil CD56bright and CD56dim, (2) CCR2 on PB and tonsil CD56bright, (3) CX3CR1 on PB CD56dim, (4) CXCR5 on tonsil CD56dim, and (5) CD94/NKG2A on PB and tonsil CD56brigh) and CD56dim NK cells. Such sHLA-G-mediated down-modulations were reverted by adding anti-HLA-G or anti-ILT2 mAbs. sHLA-G inhibited chemotaxis of (1) PB NK cells toward CXCL10, CXCL11, and CX3CL1 and (2) PB CD56bright NK cells toward CCL2 and CXCL10. IFN-γ secretion induced by NKp46 engagement was inhibited by NKG2A engagement in untreated but not in sHLA-G-treated NK cells. sHLA-G up-regulated secretion of (1) CCL22 in CD56bright and CD56dim and (2) CCL2, CCL8, and CXCL2-CXCL3 in CD56dim PB NK cells. Signal transduction experiments showed sHLA-G-mediated down-modulation of Stat5 phosphorylation in PB NK cells. In conclusion, our data delineated novel mechanisms of sHLA-G-mediated inhibition of NK-cell functions.
authors: Laboratory of Oncology, G. Gaslini Scientific Institute, Genoa, Italy. fabiomorandi@ospedale-gaslini.ge.it
authors: Fabio
authors: F
authors: Morandi
authors: Elisa
authors: E
authors: Ferretti
authors: Roberta
authors: R
authors: Castriconi
authors: Alessandra
authors: A
authors: Dondero
authors: Andrea
authors: A
authors: Petretto
authors: Cristina
authors: C
authors: Bottino
authors: Vito
authors: V
authors: Pistoia
mesh_terms: D019002:CD56 Antigen / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D059951:HLA-G Antigens / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism* / Q000502:physiology; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D020033:Protein Isoforms / Q000494:pharmacology; D012995:Solubility
chemical_list: D019002:CD56 Antigen; D018925:Chemokines; D016207:Cytokines; D059951:HLA-G Antigens; C497869:KLRD1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D020033:Protein Isoforms