ILC 2 s regulate adaptive Th 2 cell functions via PD-L 1 checkpoint control

2507 IntroductIon Innate lymphoid cells (ILCs) are now recognized as important regulators of multiple facets of immunity, spanning host defense, inflammation, metabolic homeostasis, and tissue repair (Flach and Diefenbach, 2015; ; Sonnenberg and Artis, 2015; Klose and Artis, 2016; Monticelli et al., 2016). ILCs provide the initial innate cellular responses, normally within mucosal barriers, that initiate and orchestrate systemic adaptive immunity (Klose and Artis, 2016). Group 2 ILCs (ILC2s) were first discovered as the cell sentinels responding to helminth worm infection that evoked the generation of adaptive type 2 immunity, which functioned in mediating worm rejection, allergic immunity, and repair and resolution of tissue damage (Fort et al., 2001; Fallon et al., 2006; Moro et al., 2010; Neill et al., 2010; Price et al., 2010; Saenz et al., 2010). They are predominantly found at mucosal barriers, such as human and mouse lungs, where they play roles in the initiation of protective immunity, and as effector cells during allergen-induced type 2 airway inflammation, virus infection, and antiparasite responses (Monticelli et al., 2011; Halim et al., 2012; Gorski et al., 2013). ILC2s are activated by the alarmins IL-33, IL-25, and thymic stromal lymphopoietin, which are released during tissue injury (Kim et al., 2013; Salimi et al., 2013). Upon activation, ILC2s release large amounts of type 2 cytokines IL-5 and IL-13, and also IL-4, as well as IL-9 and amphiregulin, which contribute to tissue repair (Turner et al., 2013; Monticelli et al., 2015). There is emerging evidence that ILC2s or ILC3s can directly influence Th cell polarization and functions (Hepworth et al., 2013, 2015; Mirchandani et al., 2014; von Burg et al., 2015). It has been recently described that ILC2s express MHC class II molecules and can augment Th2 polarization (Oliphant et al., 2014; Halim et al., 2016). Furthermore, ICOS and ICOS-L are activating coreceptors shown to be present on ILC2s (Maazi et al., 2015). The engagement of PD-1, primarily expressed on T cells, via its ligands PD-L1 and PD-L2 delivers an inhibitory signal to the PD-1–bearing cell (Agata et al., 1996; Freeman et al., 2000; Latchman et al., 2001; Barber et al., 2006). Inhibition via PD-1 engagement enables tumor cells to keep the adaptive immune response in check, and we have shown that parasites such as Schistosoma mansoni also use PD-L1–mediated immunosuppression to evade the adaptive immune system (Smith et al., 2004; Keir et al., 2008; Khan et al., 2015). Although described as an inhibitory interaction partner of PD-1, evidence also supports an activating function for PD-L1 (Liechtenstein et al., 2012). During Listeria monocytogenes infection, PD-L1 delivers positive costimulatory signals to innate and adaptive immune cells to protect from intracellular infection (Seo et al., 2008). PD-1 engagement can generate induced regulatory T cells, and PD-L1 costimulates T cell responses against polyclonal stimuli (Dong et al., 1999; del Rio et al., 2005; McAlees et al., 2015). So far, little is known of the involvement of PD-L1 in the control of strong type 2 immune responses. Group 2 innate lymphoid cells (ILc2s) are important effector cells driving the initiation of type 2 immune responses leading to adaptive t helper 2 (th2) immunity. Here we show that ILc2s dynamically express the checkpoint inhibitor molecule Pd-L1 during type 2 pulmonary responses. Surprisingly, Pd -L1 :Pd -1 interaction between ILc2s and cd4 t cells did not inhibit the t cell response, but Pd-L1–expressing ILc2s stimulated increased expression of GAtA3 and production of IL-13 by th2 cells both in vitro and in vivo. conditional deletion of Pd-L1 on ILc2s impaired early th2 polarization and cytokine production, leading to delayed worm expulsion during infection with the gastrointestinal helminth nippostrongylus brasiliensis. our results identify a novel Pd-L1–controlled mechanism for type 2 polarization, with ILc2s mediating an innate checkpoint to control adaptive t helper responses, which has important implications for the treatment of type 2 inflammation. ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control