Immune cells and preterm labour: do invariant NKT cells hold the key?

Whilst there is now considerable evidence that labour, both at term and preterm, is an inflammatory event associated with an immune cell influx into theutero-placental tissues (Thomson et al., 1999;Young et al., 2002; Osman et al., 2003; Gomez-Lopez et al., 2010; Rinaldi et al., 2011; Hamilton et al., 2012), the precise role that these immune cells play in the initiation of labour, either in the presence of an intrauterine infection preterm, or physiologically at term, is unclear. Previous work has shown that the infiltrating leukocytes are a major source of pro-inflammatory mediators, including interleukin (IL)-1b, IL-8, IL-6, tumour necrosis factor (TNF)-a and MMP-9 (Roh et al., 2000; Helmig et al., 2002; Young et al., 2002), suggesting that these immune cells are likely to contribute to the inflammatory response surrounding parturition. However, whether the infiltration of leukocytes is a key event in triggering the onset of parturition or merely a consequence of the heightened inflammatory signalling remains to be elucidated. In vivo animal models have been an invaluable tool to study the role of immune cells in parturition onset, where in recent years several studies have utilized either antibody-mediated immune cell depletion or genetically modified mice to investigate the function of specific immune cell populations in normal and adverse pregnancy outcomes. In this issue ofMolecular Human Reproduction, Li et al. build upon their previous findings by identifying themolecularmechanisms underlying the role of activation of invariant natural killer T (iNKT) cells in inflammationinduced preterm birth in a mouse model (Li et al., 2012, 2015). iNKTcells are a subset of T cellswhich express bothNKcell receptors and a rearrangedT cell receptor (TCR)which has a semi-invariant TCRa chain (in mice this is a Va14-Ja18 rearrangement, and in humans a Va24-Ja18 rearrangement), that pairs with a restricted set of TCRb chains (Van Kaer et al., 2013). This TCR rearrangement restricts iNKT cells to recognize self and foreign lipids presented by the MHC class 1-related protein CD1d (Brennan et al., 2013). Upon activation, iNKT cells rapidly secrete cytokines, such as interferon (IFN)-g and IL-4, and these cytokines can activate other immune cells, such as NK cells, dendritic cells, macrophages, neutrophils, B cells and T cells, and can therefore participate in a wide range of immune responses (Brennan et al., 2013). Due to their ability to produce a wide variety of cytokines and interact with other cells of the immune system, iNKT cells are often considered as a ‘bridge’ between the innate and adaptive immune systems (Boyson et al., 2008). Several studies have now reported the presence of iNKT cells in the pregnant human and mouse decidua (Ito et al., 2000; Tsuda et al., 2001; Boyson et al., 2002). iNKT cell stimulation with its specific ligand a-galactosylceramide (a-GalCer) results in both early pregnancy loss and preterm birth in mouse models (Ito et al., 2000; Boyson et al., 2006). Additionally, Ja18 KO mice, which have no iNKT cells, have a reduced rate of lipopolysaccharide (LPS)-induced early pregnancy loss and LPS-induced preterm birth (Li et al., 2012, 2013). In this issue, Li et al. report that adoptive transfer of decidual iNKT cells to Ja18 KO mice promotes LPS-induced preterm birth and, by using various neutralizing antibodies, demonstrate that decidual iNKT cell activation is regulated by TLR-4-mediated signalling pathways, IL-12 and IL-18 secretion, and endogenous glycolipid antigens presented by CD1d. In women, neutrophils are proposed to play a role in cervical ripening (Bokström et al., 1997) and have been shown to infiltrate into the myometrium and cervix in association with term labour (Thomson et al., 1999; Osman et al., 2003). Furthermore, neutrophil infiltration has been specifically associated with infection-induced preterm labour. Hamilton et al. recently reported increased decidual neutrophil infiltration in women with infection-associated preterm labour, compared with women in either idiopathic or normal term labour (Hamilton et al., 2012). A similar neutrophil influx has been reported in mouse models of inflammation-induced preterm labour (Shynlova et al., 2013; Rinaldi et al., 2014). However, in these models, neutrophil depletion in mice has been reported to have no effect on the timing of delivery either in normal term labour (Timmons and Mahendroo, 2006) or in models of CpG-oligodeoxynucleotide (CpG ODN; a TLR-9 agonist)induced (Thaxton et al., 2009; Sun et al., 2013) and LPS-induced preterm birth (Rinaldi et al., 2014), suggesting that neutrophil infiltration is not required for the onset of preterm labour. The role of mast cells in the onset of parturition has also been investigated (Menzies et al., 2011). Mast cells have been identified in the pregnant human and mouse uterus and cervix (Thomson et al., 1999; Naik et al., 2004; Garfield et al., 2006; Menzies et al., 2012); and there is evidence indicating that degranulation of mast cells can induce myometrial