Interaction with mast cells induces the proliferation of iNKT cells and the secretion of IFN-, IL-4, and IL-13 (46), suggesting that NKT cells may play a role during allergic responses

Interaction with mast cells induces the proliferation of iNKT cells and the secretion of IFN-, IL-4, and IL-13 (46), suggesting that NKT cells may play a role during allergic responses. that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells Ginsenoside Rh2 to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported Ginsenoside Rh2 by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion. gene family in humans comprises five members (gene (with two loci, and stimulation of iNKT cells. Upon administration, GalCer is taken by APCs, such as DCs or macrophages, and presented on CD1d to iNKT cells (32). This process leads to a quick activation of iNKT cells in a matter of a few hours (contrary to what is required by conventional T cells), inducing the secretion of several cytokines (32). An early secretion of IL-4 and a late secretion of IFN- (modulating inflammation, in this way) along with the expression of different activation markers also detected in conventional T cells, such as CD25 and CD69, are observed (33). Remarkably, iNKT Mmp17 Ginsenoside Rh2 cell activation seems to induce a transient internalization of the TCR and downregulation of NK1.1, which makes it difficult to detect this population at early time points after activation (34). Treatment with GalCer induces internalization of the TCR starting at 1 h poststimulation, reaching a peak at 8 to 12 h poststimulation, and returning to basal levels 24 to Ginsenoside Rh2 48 h after the stimulation. Interestingly, this behavior was detected both and in the mouse model (34). Expression of the programmed death-1 (PD-1) receptor is increased on the surfaces of iNKT cells, which can bind to PD-L1 and PD-L2 (molecules expressed on the surfaces of APCs and other immune cells), inducing an anergic state in NKT cells (34, 35). Along with the secretion of cytokines and the changes in surface marker expression, iNKT cells also rapidly proliferate, reaching a peak at day 3 or 4 4 poststimulation (Fig. 2) (36). Two of the most significant elements of the modulation of the innate response by iNKT cells are the transactivation of NK cells and the modulation of the cytokine secretion pattern of DCs. Historically, cross talk between iNKT cells, NK cells, and DCs was one of the first topics to be studied, and the mechanisms underlying these interactions will be discussed in the following paragraphs (Fig. 2). Upon stimulation with GalCer, iNKT cells induce intense and swift activation and proliferation of NK cells (37, 38). Transactivation (defined as a nondirected activation) of NK cells by iNKT cells is an IFN–dependent process that is also enhanced by IL-12 produced by DCs (38). NK cell activation provides an additional boost in IFN- secretion, enhancing their cytotoxic functions, which is crucial for the clearance of viral infections and the killing of tumor cells. It is important to note that both NK and iNKT cells express the IL-12 receptor (IL-12R) on their surfaces, rendering them responsive to this cytokine (39). Among the major IL-12 producers are DCs, and iNKT cells have been shown to promote the secretion of IL-12 by DCs. Secretion of IL-12 is induced in a CD40/CD40L-dependent manner, implying a necessary physical interaction between DCs and iNKT cells (32). The establishment of such an interaction triggers increased expression of the IL-12R by iNKT cells, thereby promoting a positive feedback loop between iNKT cells and DCs: once stimulated with IL-12, NKT cells secrete IFN-, which in turn stimulates DCs to secrete more IL-12 (32). This type of positive feedback is also observed between NK cells and DCs during localized bacterial infections, leading to massive tissue damage (Fig. 2) (39). Since iNKT cells are a source of IFN-, they can enhance phagocytosis by macrophages, as also described for NK cells Ginsenoside Rh2 and T cells (40). Additionally, IFN–secreting iNKT cells can.