Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation.
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.
Michel
Marie-Laure
ML
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.
Mendes-da-Cruz
Daniella
D
Keller
Alexandre Castro
AC
Lochner
Matthias
M
Schneider
Elke
E
Dy
Michel
M
Eberl
Gérard
G
Leite-de-Moraes
Maria C
MC
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*
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