Sensitization and challenge of mice with Ovalbumin (OVA)-Alum and papain-OVA also showed normal expansion of Th2 responses, while genetically DC-depleted animals showed severely impaired responses (Kim et al

Sensitization and challenge of mice with Ovalbumin (OVA)-Alum and papain-OVA also showed normal expansion of Th2 responses, while genetically DC-depleted animals showed severely impaired responses (Kim et al., 2013b; Ohnmacht et al., 2010). Notch receptor ligands on DCs (de Kleer et al., 2016; Willart et al., 2012). Although these surface molecules can promote Th2 polarization, blockade of any of these pathways doesnt necessarily affect Th2 polarization in all models studied (Chu et al., 2013; Tu et al., 2005). At the T cell level, Th2 differentiation starts with induction of a TCR driven activation of GATA3 transcription factor, and induction of STAT5 phosphorylation, triggered by IL-2, or TSLP (Zhang et al., 1997). Further commitment to the Th2 lineage, is greatly enhanced by STAT-6 phosphorylation in response to IL-4R triggering by the polarizing cytokine IL-4 (Shimoda et al., 1996). Since this cytokine is not made by DCs themselves, a lot of effort has been placed in trying to elucidate the cellular source of the initial burst of IL-4 production. Innate basophils, eosinophils and ILC2s have all been proposed to provide this early source of IL-4 in trans, and the fact that these cells can be found in the T cell area early in an immune response makes this a possible scenario (Ben-Sasson et al., 1990; Hammad et al., 2010; Sokol et al., 2008; van Rijt et al., 2003). Antigens that lead to low dose MHCII-peptide display or low affinity ligands for TCR triggering, also tend to favour Th2 polarization. The potential of basophils and eosinophils to simultaneously produce IL-4 and to display low dose peptide-MHCII led some investigators to suggest that type 2 immune responses are preferentially and even exclusively induced by these non-professional APCs and helminth infection and immunization with the Th2 adjuvant alum, IL-4+ TFH development was also shown to depend on Notch ligand expression by conventional DCs and T cell intrinsic Notch signalling, whereas Th2 development did not (DellAringa and Reinhardt, 2018). A big question in the field is whether subsets of cDC2s exist Tedalinab that would preferentially induce TFH over effector Th2 immune responses. Recent data also suggest that the potential of cDC2s to induce pure Th2 immunity or a mixed Th2/Th17 type of response is tightly regulated by cell intrinsic mechanisms, including fine tuning of TLR signalling pathways and metabolic programming (Sinclair et al., 2017; Vroman et al., 2017). Understanding induction of such mixed Th2/Th17 responses is important, since this profile is often seen in steroid-resistant difficult-to-treat allergic diseases. B cells can induce Th2 and TFH responses and elicit help from CD4+ T cells in an MHC-II dependent manner, but using T cell antigen receptor Tedalinab (TCR) transgenic Tedalinab 1-DER mice that react to the type 2 antigen Der p 1 of the house dust mite (Dullaers et al., 2016). However, there are some recent data to suggest that antigen presentation by B cells in the HDM model controls the rate of formation of T resident memory cells versus IL-4 producing TFH cells, since these are mutually Rabbit Polyclonal to ATRIP exclusive cell fates for antitehn-reactive na?ve T cells Tedalinab (Ballesteros-Tato et al., 2016; Hondowicz et al., 2016). Thus, mice lacking B cells had less TFH cells and an increase Tedalinab in TRM cells, explaining why B cell deficient mice had increased airway inflammation when challenged with HDM inhalation long after the priming period (Hondowicz et al., 2016). However, further studies are warranted to better understand B-cell induction of Th2 cells in vivo. Macrophages capture large amounts of type 2 allergens and become M2 polarized in type 2 immune responses such as helminth infection and asthma in mouse and man (Girodet et al., 2016; Reece et al., 2006). In the lungs, clodronate.