Platelet-derived TGF-βI mediates the down-modulation of NKG2D expression and may be responsible for impaired natural killer (NK) cytotoxicity in women with endometriosis

Abstract

Study question: Does platelet-derived transforming growth factor-b1 (TGF-βI) have any role in the reduced cytotoxicity of natural killer (NK) cells in women with endometriosis? summary answer: Platelet-derived TGF-βI suppresses the expression of NK Group 2, Member D (NKG2D) on NK cells, resulting in reduced cytotoxicity in women with endometriosis, but neutralization of TGF-βI reverses the reduction. what is known already: NKcells are cytotoxic lymphocytes that play an important role in peritoneal immune surveillance, and their function is known to be impaired in women with endometriosis. There is increased platelet aggregation in endometriotic lesions and increased platelet activation rate in the peripheral blood inwomen with endometriosis, yet activated platelets release copiousTGF-βI, which is known to be a potent immunosuppressive molecule that suppresses NK cell function and NKG2D expression. study design, size, duration: Cross-sectional clinical studies of 30 women with endometriosis and 33 women without endometriosis and in vitro experimentation with and without TGF-βI blockade. participants/materials, setting, methods: Peritoneal fluid (PF) samples frompremenopausal women with endometriosis and age- and menstrual phase-matched controls were collected. Platelet count, white blood cell (WBC) count, mean platelet volume (MPV), platelet activation rate,TGF-βI concentration, expression levels ofNKG2DonNKcells in the PFwere evaluated. The apoptosis of freshly isolated NKcells treated with PF fromwomenwith endometriosis, theNKcytotoxicity andNKG2Dexpression treated with PF in the presence or absence of an anti-TGF-βI antibody were also determined. main results and the role of chance: The platelet count,WBCcount, MPV, platelet activation rate and the TGF-βI concentration in the PF from women with endometriosis were significantly elevated when compared with those of women without endometriosis. The TGF-βI concentration correlated positively with the platelet activation rate (r = 0.59, P , 0.01), suggesting that activated platelets are responsible, at least in part, for the increased TGF-βI concentration. The cytotoxicity of freshly isolated NK cells treated with PF of women with endometriosis is significantly reduced when compared with that of women without endometriosis. Both the platelet activation rate and the TGF-βI concentration in the PF correlated negatively with theNKG2Dexpression inNKcells isolated from the PF (r = 20.36, P , 0.01, and r = 20.45, P , 0.01, respectively). In addition, the NKG2D expression level and the cytotoxicity in freshly isolated NK cells were found to be significantly reduced if co-cultured with PF from women with endometriosis, but the TGF-βI blockade effectively reverses the reduction. limitations, reasons for caution: This study is limited by the cross-sectional nature of the study. wider implications of thefindings: NKG2Dis knownto potentlyactivateNKcells, sopotent that itevenoverrides inhibitory signals transduced by other inhibitory receptors. This is the first time we demonstrate that platelet-derived TGF-βImay be responsible for reducedNKG2D expression aswell as reduced cytotoxicityofNKcells inwomenwith endometriosis.This study provides yet another piece of evidence that platelets play critical roles in the development of endometriosis, and anti-platelet treatment should improve NK cell functionality in treating endometriosis. Equally important, this study highlights the critical role of the lesion microenvironment in shaping NK cell-mediated anti-endometriotic immunity. study funding/competing interests: This research was supported in part by grants 81270676 (S.-W.G.), 81471434 (S.-W.G.), 81530040 (S.-W.G.), and 81370695 (X.L.) from the National Natural Science Foundation of China, and grant 2013ZYJB0019 (X.L.) from Shanghai Municipal Commission of Health and Family Planning. None of the authors has anything to disclose.