Additionaly, it has been shown that MDSCs and additional tolerogenic myeloid lineage cells can promote the induction of Treg cells.90,91 Hence, activated iNKT cells might induce Treg cells either directly or indirectly via tolerogenic myeloid cells. that activation of Rabbit Polyclonal to VEGFR1 (phospho-Tyr1048) NKT cells with synthetic lipid antigens can, at least under particular experimental conditions, guard mice against the development of MS-like disease. Although mechanisms of this safety remain to be fully investigated, current evidence suggests that it entails interactions with additional immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong basis for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. However, additional pre-clinical and medical studies will be required to bring this goal to fruition. chain.11 Glycosphingolipids and diacylglycerols that can activate iNKT cells have been isolated from numerous microbial pathogens (e.g. and varieties). A Bupivacaine HCl lot of argument in the field offers focused on the endogenous antigens that travel the development and function of iNKT cells.12 Although it has been long assumed that mammalian cells only produce (IFN-and become cytotoxic, B cells to produce antibodies, and dendritic cells (DCs) to become activated.7,23 Activation of iNKT cells can also influence the differentiation of T helper (Th) cells, typically skewing the response towards Th2 cytokine production, especially when multiple gene section of murine iNKT cells. These findings suggested that susceptibility of SJL/J mice to EAE might somehow be linked to alterations in the iNKT cell compartment, a possibility that remains to be validated. One study investigated the fate of iNKT cells in the CNS of mice with EAE and found that figures remain unchanged as compared with naive animals.67 The effects of CD1d- and Jand production by iNKT cells, Bupivacaine HCl and disease safety involved IL-10 production by MDSCs. These findings are therefore consistent with the previously recognized part of IFN-in the protecting effects of -GalCer against EAE.77,78 Because MDSCs can give rise to mature myeloid cells, an appealing possibility is that the immunosuppressive DCs and M2 macrophages that build up in response to -GalCer treatment during EAE induction are derived from splenic MDSCs. Studies on -GalCer treatment of autoimmune diseases other than EAE might Bupivacaine HCl provide further insight into the protective effects of iNKT cell activation in EAE.23,25 In particular, a study on diabetes in NOD mice88 and another on experimental myasthenia gravis in C57BL/6 mice89 offers offered evidence for a role of Foxp3+ Treg cells in disease protection afforded by -GalCer.27 A possible part for Treg cells in the protective effects of iNKT cell antigens on EAE is therefore appealing. With this context, iNKT cells produce cytokines such as IL-2 and transforming growth element-, which might directly contribute to the induction of Treg cells. Additionaly, it has been demonstrated that MDSCs and additional tolerogenic myeloid lineage cells can promote the induction of Treg cells.90,91 Hence, activated iNKT cells might induce Treg cells either directly or indirectly via tolerogenic myeloid cells. Collectively, these findings suggest cooperative relationships between iNKT cells, tolerogenic myeloid cells and Treg cells in protecting mice against EAE and potentially additional autoimmune and inflammatory diseases. A proposed model for the protecting effects of -GalCer and related glycolipids against EAE is definitely depicted in Fig.?Fig.22. Open in a separate window Number 2 Proposed model for the capacity of -galactosylceramide (-GalCer) and related invariant natural killer T (iNKT) cell antigens to protect mice against experimental autoimmune encephalomyelitis. -GalCer-activated iNKT cells produce a variety of cytokines that can promote T helper type 2 (Th2) deviation of autoreactive T-cell reactions, Foxp3+ regulatory T (Treg) cells, and immunosuppressive immature [e.g. myeloid-derived suppressor cells (MDSCs)] and adult [e.g. dendritic cells (DCs), M2 macrophages] myeloid cells. Tolerogenic myeloid lineage cells may also promote the induction of Treg cells. In turn, Th2 cells, Treg cells and suppressive myeloid cells suppress the generation and/or function of pathogenic autoantigen-specific Th1, Th17 and cytotoxic T cells.