title: TLR-induced cytokines promote effective proinflammatory natural Th17 cell responses.
abstract: Naive CD4 lymphocytes undergo a polarization process in the periphery to become induced Th17 (iTh17) cells. Using retinoic acid-related orphan receptor γt (RORγt)-gfp mice, we found that RORγt and the transcription factor promyelocytic leukemia zinc finger (PLZF) are valuable new markers to identify the recently described natural Th17 (nTh17) cell population. nTh17 cells are thymically committed to promptly produce large amounts of IL-17 and IL-22. In this study, we show that, in addition to responding to TCR cross-linking, nTh17 cells secrete IL-17 and IL-22 when stimulated with IL-23 plus IL-1β, either in recombinant form or in supernatants from TLR4-activated dendritic cells. This innate-like ability of RORγt(+) nTh17 cells to respond to TLR4-induced cytokines was not shared by iTh17 cells. The other distinct properties of RORγt(+) nTh17 cells are their high expression of PLZF and their absence from lamina propria; iTh17 cells are found therein. RORγt(+) nTh17 cells are present in the thymus of germ-free RORγt-gfp and IL-6(-/-) RORΓ: t-gfp mice, indicating that these cells do not require symbiotic microbiota or IL-6 for their generation. Finally, we found that PLZF(+)RORγt(+) nTh17 cells represent one of the primary IL-17-producing innate-like T cell populations in a TLR7 imiquimod model of psoriasis-like disorder, indicating their involvement in this kind of lesion. Collectively, our results reveal RORγt and PLZF as characteristic markers for identifying nTh17 cells and demonstrate one of their novel properties: the ability to respond promptly to TLR-dependent proinflammatory stimuli without TCR engagement, placing them as members of the innate-like T cell family.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France; Institut Necker Enfants Malades, INSERM Unité Mixte de Recherche 1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75015 Paris, France;
authors.forename: Bérangère
authors.initials: B
authors.lastname: Massot
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France; Institut Necker Enfants Malades, INSERM Unité Mixte de Recherche 1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75015 Paris, France;
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Michel
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France;
authors.forename: Séverine
authors.initials: S
authors.lastname: Diem
authors.affiliation: Institut Pasteur, Lymphoid Tissue Development Unit, 75724 Paris, France; and.
authors.forename: Caspar
authors.initials: C
authors.lastname: Ohnmacht
authors.affiliation: Institut Imagine, INSERM Unité Mixte de Recherche 1163, Laboratoire Activation Lymphocytaire et Susceptibilité à l'EBV, Hôpital Necker Enfants-Malades, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France; Institut Necker Enfants Malades, INSERM Unité Mixte de Recherche 1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75015 Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.affiliation: Institut Pasteur, Lymphoid Tissue Development Unit, 75724 Paris, France; and.
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France; Institut Necker Enfants Malades, INSERM Unité Mixte de Recherche 1151, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8253, 75015 Paris, France; maria.leite-de-moraes@parisdescartes.fr.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Leite-de-Moraes
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology; D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D000077271:Imiquimod; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011565:Psoriasis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D016207:Cytokines; D051741:Kruppel-Like Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C513267:Zbtb16 protein, mouse; D000077271:Imiquimod