title: Signal Strength and Metabolic Requirements Control Cytokine-Induced Th17 Differentiation of Uncommitted Human T Cells.
abstract: 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.
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy; Forschungszentrum für Immunwissenschaften, Charité Universitätsmedizin Berlin, 10115 Berlin, Germany; Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany;
authors.forename: Ilko
authors.initials: I
authors.lastname: Kastirr
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy;
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Crosti
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Maglie
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy;
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: Forschungszentrum für Immunwissenschaften, Charité Universitätsmedizin Berlin, 10115 Berlin, Germany; Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany;
authors.forename: Bodo
authors.initials: B
authors.lastname: Steckel
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Moro
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy; and.
authors.forename: Massimilliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy; Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, 20122 Milan, Italy; geginat@ingm.org.
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D008297:Male; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology; D054399:Receptors, CCR6 / Q000276:immunology; D018123:Receptors, Interleukin / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C106311:CCR6 protein, human; C573415:IFNG protein, human; C515500:IL23R protein, human; C539900:RORC protein, human