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IL-17 production defines Thl7 cells, which orchestrate immune responses and autoimmune diseases. Human Thl7 cells can he efficiently generated with appropriate cytokines from precommitted precursors, but the requirements of uncommitted T cells are still ill defined. In standard human Thl7 cultures, IL-17 production was restricted to CCR6+CD45RA+ T cells, which expressed CD95 and produced IL-17 ex vivo, identifying them as Thl7 memory stem cells. Uncommitted naive CD4+ T cells upregulated CCR6, RORC2, and IL-23R expression with Thl7-promoting cytokines but in addition required sustained TCR stimulation, late mammalian target of rapamycin (mTOR) activity, and HIF-lα 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-γ production, but these cytokines had also unique metabolic requirements. Thus, glucose promoted IL-12-independent Thl differentiation, whereas aromatic amino acid-derived AHR ligands were selectively required for IL-22 production. The identification of Thl7 memory stem cells and the stimulation requirements for induced human Th 17/22 differentiation have important implications for T cell biology and for therapies targeting the mTOR pathway. [ABSTRACT FROM AUTHOR]

IL-21 promotes Thl7 differentiation, and Thl7 cells that upregulate T-bet, IFN-γ, 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 Thl and Thl7 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4+ T cells, it inhibited the generation of Thl effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Thl7 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL- 10 secretion but inhibited IFN-γ and GM-CSF production in developing Thl7 cells, and consequently prevented the generation of polyfunctional Thl/17 effector cells. Moreover, in Thl7 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 Thl7 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Thl/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. [ABSTRACT FROM AUTHOR]