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,...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2015-10, Vol.195 (8), p.3617-3627
Main Authors: Kastirr, Ilko, Crosti, Mariacristina, Maglie, Stefano, Paroni, Moira, Steckel, Bodo, Moro, Monica, Pagani, Massimilliano, Abrignani, Sergio, Geginat, Jens
Format: Article
Language:English
Subjects:
Cell Differentiation - immunology
Female
Humans
Immunologic Memory - physiology
Interferon-gamma - immunology
Interleukin-22
Interleukins - immunology
Male
Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology
Receptors, CCR6 - immunology
Receptors, Interleukin - immunology
Signal Transduction - immunology
Th17 Cells - cytology
Th17 Cells - immunology
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Summary: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-1α to produce IL-17. However, in standard high-density 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 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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1501016