Xiang-Ping Yang

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.

Signal transduction pathways and transcriptional regulation in Th17 cell differentiation

Over the last decade, our understanding of helper/effector T cell differentiation has changed dramatically. The discovery of interleukin (IL-)17-producing T cells (Th17) and other subsets has changed our view of T cell-mediated immunity. Characterization of the signaling pathways involved in the Th17 commitment has provided exciting new insights into the differentiation of CD4+ T cells. Importantly, the emerging data on conversion among polarized T helper cells have raised the question how we should view such concepts as T cell lineage commitment, terminal differentiation and plasticity. In this review, we will discuss the current understanding of the signaling pathways, molecular interactions, and transcriptional and epigenetic events that contribute to Th17 differentiation and acquisition of effector functions.

Helper T-cell differentiation and plasticity: insights from epigenetics

CD4+ T cells have critical roles in orchestrating immune responses to diverse microbial pathogens. This is accomplished through the differentiation of CD4+ T helper cells to specialized subsets in response to microbial pathogens, which evoke a distinct cytokine milieu. Signal transducer and activator of transcription family transcription factors sense these cytokines and they in turn regulate expression of lineage‐defining master regulators that programme selective gene expression, resulting in distinctive phenotypes. However, phenotype and restricted gene expression are determined not only by the action of transcription factors; chromatin accessibility is required for these factors to exert their effect. Technical advances have greatly expanded our understanding of transcription factor action and dynamic changes in the epigenome that accompany cellular differentiation. In this review, we will discuss recent progress in the understanding of how cytokines influence gene expression and epigenetic modifications, and the impact of these findings on our views of helper cell lineage commitment and plasticity.

EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion

The roles of EZH2 in various subsets of CD4+ T cells are controversial and its mechanisms of action are incompletely understood. FOXP3-positive Treg cells are a critical helper T cell subset, and dysregulation of Treg generation or function results in systemic autoimmunity. FOXP3 associates with EZH2 to mediate gene repression and suppressive function. Herein, we demonstrate that deletion of Ezh2 in CD4 T cells resulted in reduced numbers of Treg cells in vivo and differentiation in vitro and an increased proportion of memory CD4 T cells in part due to exaggerated production of effector cytokines. Furthermore, we found that both Ezh2-deficient Treg cells and T effector cells were functionally impaired in vivo: Tregs failed to constrain autoimmune colitis and T effector cells neither provided a protective response to T. gondii infection nor mediated autoimmune colitis. The dichotomous function of EZH2 in regulating differentiation and senescence in effector and regulatory T cells helps to explain the apparent existing contradictions in literature.

Function of JAKs and STATs in Lymphocytes: Bench to Bedside

There are four members of Janus Kinase family (JAK-1, -2, -3 and TYK2) and seven members of STAT family (STAT-1, -2, -3, -4, -5a, -5b and -6) in the mammalian genome, each with unique functions in immune cells. Consistent with studies in mice, genetic evidence in humans has strongly linked the JAK/STAT pathway to primary immunodeficiencies, infection, autoimmunity and cancers. The following chapter will discuss the key role played by JAKs and STATs in the lymphocytes, with special emphasis on helper T cells, which are not only critical mediators of pathogenic inflammation, but also an outstanding model system for investigating JAK/STAT biology. Recent conceptual and technological advances will be highlighted, particularly those relating to human disease and the generation of JAK/STAT based therapeutics.