Mandy J. McGeachy

Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity. Although crucial for TH17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.

Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (TH-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of TH-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, TH-17 development was stalled at the early activation stage. TH-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor α-chain. These defects were associated with less proliferation; consequently, fewer effector TH-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.

Th17 Cell Differentiation: The Long and Winding Road

The characterization of the new lineage of IL-17-producing CD4+ T helper (Th17) cells has revolutionized our current understanding of T cell-mediated immunity. Over the past five years, there have been many twists and turns as the pathways that lead to Th17 cell differentiation have been elucidated. Not least of these was the discovery that TGF-beta is a crucial cytokine for Th17 cell development, suggesting that Th17 and regulatory T cell subsets share reciprocal developmental pathways during the pathogenesis or control of inflammation. This review aims to bring together the observations that have formed current opinion on factors that promote and contain Th17 cell development, in both mouse and man. Unresolved controversies in this field are also discussed: For example, IL-23 is absolutely required for disease pathogenesis in many models of Th17-cell-mediated autoimmunity, yet its role in Th17 cell development is relatively unclear.

The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation

Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.

The link between IL-23 and Th17 cell-mediated immune pathologies

IL-23--produced by dendritic cells--and Th17 cells have both been identified as major factors involved in autoimmune inflammation, yet their relationship with each other remains controversial. This review aims to describe the initial discovery of Th17 cells, their subsequent characterization as a unique T helper subset in mouse and man, as well as the mechanisms involved in regulating these cells. Finally, the roles of IL-23 in inflammatory diseases in relation to Th17 function will be discussed.

Cytokines that regulate autoimmunity.

Recent advances have revealed new insights in cytokine regulation of inflammatory responses. TGFbeta acting together with pro-inflammatory cytokines such as IL-6 promotes lineage commitment of RORgamma-dependent Th17 cells. IL-23--a member of the IL-12 family--activates the effector function of Th17 cells to promote skin, lung, and mucosal immunity. However, when dysregulated, these cells are important players in autoimmune inflammation. Unexpectedly, IL-27--another IL-12 family member--plays an opposing role by inducing IL-10 production as well as downregulating both Th17 and Th1-mediated immune pathologies.