Soluble HLA-I-mediated secretion of TGF-beta1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity.
Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-beta1. CD8+KIR- NK cell clones secreted TGF-beta1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-beta1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-beta1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Also, TGF-beta1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-beta1. Furthermore, TGF-beta1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-beta1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-beta1 release.
Ghio
Massimo
M
Department of Internal Medicine, University of Genoa and San Martino Hospital of Genoa, 16132-Italy.
Contini
Paola
P
Negrini
Simone
S
Boero
Silvia
S
Musso
Alessandra
A
Poggi
Alessandro
A
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D005434:Flow Cytometry; D006680:HLA Antigens / Q000378:metabolism*; D015236:HLA-C Antigens / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000378:metabolism; D054342:Receptors, KIR2DL1 / Q000378:metabolism; D054343:Receptors, KIR2DL2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016827:CD8 Antigens; D006680:HLA Antigens; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; C039966:HLA-C*04 antigen; C093100:KIR2DL1 protein, human; C515077:KIR2DL2 protein, human; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma