In this model, the IL-12 family members had strikingly differential roles: while IL-23 was nonredundant for the development of colitis, only IL-12 perpetuated the LGK-974 manufacturer accompanying

systemic inflammatory response and wasting disease. The cell type responsible for the CD40-driven intestinal inflammation was not identified until recently, when Powrie and colleagues showed that a novel population of gut-resident Thy1+ Sca1+ RORγt+ innate lymphoid cells (ILCs) responds to IL-23 [98]. Mechanistically, IL-23R signaling activated expression of IFN-γ and IL-17 by ILCs, and neutralization of these cytokines strongly ameliorated the disease course [95]. Depletion of ILCs using an anti-Thy1 antibody almost abrogated colon inflammation, while the systemic wasting disease remained unaffected. When comparing the action of IL-23 on αβ T cells, γδ T cells, and ILCs, there seems to be a remarkable conservation in function, with all three cell types responding to IL-23 by production of proinflammatory cytokines such as IL-17, IL-22, and IFN-γ (Fig. 2). Thus, innate cells such as ILCs might be part of an early, immediate tissue inflammatory response, while T cells respond to IL-23 later in an antigen-dependent fashion. Of note, the (at least partially) IL-23-driven effector cytokines IL-17 and IFN-γ seem to play

completely divergent roles in different autoimmune settings: while neither of these cytokines are essential for disease INK 128 cost progression in EAE [55, 56, 99], their neutralization in innate IBD strongly ameliorated the disease [98]. These differential results of cytokine depletion do not come as a surprise Obatoclax Mesylate (GX15-070) given the distinctive lymphocyte composition in the brain and the gut, but emphasize that the downstream effects of IL-23R engagement are highly dependent on the targeted cell population and the target organ. Very recently, it has been suggested that ILCs could also contribute to skin inflammation by IL-23-driven production of IL-22 [84]. However, whether IL-23-mediated activation

of ILCs is involved in additional immunopathologies remains to be determined and requires a more thorough understanding of the function of ILC populations during immune responses. When considering self-reactivity of the immune system and autoimmune destruction of healthy tissues, one must also consider the beneficial aspect of anti-tumor immunity [100]. T cells are known to play an important role in early-stage control of tumor growth, and some T-cell-derived cytokines such as IL-17 and IFN-γ are thought to have anti-tumor activity. For this reason, IL-23 has also been studied for its potential function during an anti-tumor response. Initial reports using IL-23-transfected tumor cell lines suggested an anti-tumorigenic function similar to that of IL-12 [101].