title: Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation.
abstract: Invariant natural killer T (iNKT) cells constitute a subpopulation of T cells that recognize glycolipids presented by CD1d molecules. They are characterized by their prompt production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), which enables them to modulate diverse immune responses. Recently, we enlarged this concept by identifying a distinct IL-17-producing iNKT cell subset, named iNKT17 cells. The mechanisms leading to the acquisition of this new iNKT cell activity are unknown. Herein we show that IL-17-producing iNKT cells are already present in the thymus, predominantly among a subset regarded so far as an immature stage of thymic iNKT cell development, the CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) cells. Using EGFP reporter mice, we demonstrate that the transcription factor ROR-gammat is critical for the thymic differentiation of this subset because only ROR-gammat(pos) iNKT cells are capable of massively secreting IL-17. Moreover, IL-17-producing CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) thymic iNKT cells have reached a mature differentiation stage because they fail to generate other cell subsets in fetal thymic organ culture. Conversely, thymic ROR-gammat(neg) iNKT cell precursors give rise to progeny, but acquire neither ROR-gammat expression nor the ability to secrete IL-17. In conclusion, our findings demonstrate an alternative thymic pathway leading to the development of iNKT17 cells that requires ROR-gammat expression.
authors.affiliation: Faculté de Médecine, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Hôpital Necker, Université Paris Descartes, 161 rue de Sèvres, 75743, Paris, Cedex 15, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Michel
authors.forename: Daniella
authors.initials: D
authors.lastname: Mendes-da-Cruz
authors.forename: Alexandre Castro
authors.initials: AC
authors.lastname: Keller
authors.forename: Matthias
authors.initials: M
authors.lastname: Lochner
authors.forename: Elke
authors.initials: E
authors.lastname: Schneider
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.forename: Maria C
authors.initials: MC
authors.lastname: Leite-de-Moraes
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005699:Galactosylceramides / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D005699:Galactosylceramides; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; C493154:alpha-galactosylceramide; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins