Reverse plasticity : TGF-β and IL-6 induce Th1-to-Th17-cell transdifferentiation in the gut

Th17 cells are a heterogeneous population of pro-inflammatory T cells that have been shown to mediate immune responses against intestinal bacteria. Th17 cells are highly plastic and can transdifferentiate to Th1/17 cells or unconventional Th1 cells, which are highly pathogenic in animal models of immune-mediated diseases such as inflammatory bowel diseases. A recent European Journal of Immunology article by Liu et\ua0al. (Eur. J. Immunol. 2015. 45:1010\u20131018) showed, surprisingly, that Th1 cells have a similar plasticity, and could transdifferentiate to Th17 cells. Thus, IFN-\u3b3-producing Th1 effector cells specific for an intestinal microbial antigen were shown to acquire IL-17-producing capacities in the gut in a mouse model of colitis, and in response to TGF-\u3b2 and IL-6 in vitro. TGF-\u3b2\ua0induced Runx1, and together with IL-6 was shown to render the ROR-\u3b3t and IL-17 promoters in Th1 cells accessible for Runx1 binding. In this commentary, we discuss how this unexpected plasticity of Th1 cells challenges our view on the generation of Th1/17 cells with the capacity to co-produce IL-17 and IFN-\u3b3, and consider possible implications of this Th1-to-Th17-cell conversion for therapies of inflammatory bowel diseases and protective immune responses against intracellular pathogens

The CD4-centered universe of human T cell subsets

Humans are continuously exposed to a high number of diverse pathogens that induce different types of immune responses. Primary pathogen-specific immune responses generate multiple subsets of memory T cells, which provide protection against secondary infections. In recent years, several novel T cell subsets have been identified and have significantly broadened our knowledge about T cell differentiation and the regulation of immune responses. At the same time the rapidly growing number of incompletely characterized T cell subsets has also generated some controversies. We therefore review here the current knowledge on features and functions of human \u3b1/\u3b2 T cell subsets, focusing on CD4+ T cells classified according to cytokine production and tissue localization. The principal helper and regulatory T cell subsets can be identified by a limited number of relevant surface markers, which are an integral part of the T cell differentiation programs because they are directly induced by the relevant lineage-defining transcription factors. In vivo occurring human T cell subsets can thus be purified directly ex vivo from relevant tissues for molecular and functional studies, and represent not only an ideal model to study T cell differentiation, but they also offer important clinical opportunities. \ua9 2013 Elsevier Ltd

Signal strength and metabolic requirements control cytokine-induced Th17 differentiation of uncommitted human T cells

IL-17 production defines Th17 cells, which orchestrate immune responses and autoimmune diseases. Human Th17 cells can be efficiently generated with appropriate cytokines from precommitted precursors, but the requirements of uncommitted T cells are still ill defined. In standard human Th17 cultures, IL-17 production was restricted to CCR6+ CD45RA+ T cells, which expressed CD95 and produced IL-17 ex vivo, identifying them as Th17 memory stem cells. Uncommitted naive CD4+ T cells upregulated CCR6, RORC2, and IL-23R expression with Th17-promoting cytokines but in addition required sustained TCR stimulation, late mammalian target of rapamycin (mTOR) activity, and HIF-1\u3b1 to produce IL-17. However, in standard highdensity cultures, nutrients like glucose and amino acids became progressively limiting, and mTOR activity was consequently not sustained, despite ongoing TCR stimulation and T cell proliferation. Sustained, nutrient-dependent mTOR activity also induced spontaneous IL-22 and IFN-\u3b3 production, but these cytokines had also unique metabolic requirements. Thus, glucose promoted IL-12-independent Th1 differentiation, whereas aromatic amino acid-derived AHR ligands were selectively required for IL-22 production. The identification of Th17 memory stem cells and the stimulation requirements for induced human Th17/22 differentiation have important implications for T cell biology and for therapies targeting the mTOR pathway

IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells

IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-\u3b3, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4+central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4+T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL- 10 secretion but inhibited IFN-\u3b3 and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases