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Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation

Michel, Marie-Laure, Mendes-da-Cruz, Daniella, Keller, Alexandre Castro, Lochner, Matthias, Schneider, Elke, Dy, Michel, Eberl, Gérard, Leite-de-Moraes, Maria C.
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.50 pp. 19845-19850
T-lymphocytes, cell differentiation, glycolipids, immatures, immune response, interferon-gamma, interleukin-17, interleukin-4, mice, organ culture, progeny, thymus gland, transcription factors
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-γ (IFN-γ), 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 tetramerposCD44posNK1.1negCD4neg cells. Using EGFP reporter mice, we demonstrate that the transcription factor ROR-γt is critical for the thymic differentiation of this subset because only ROR-γtpos iNKT cells are capable of massively secreting IL-17. Moreover, IL-17-producing CD1d tetramerposCD44posNK1.1negCD4neg 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-γtneg iNKT cell precursors give rise to progeny, but acquire neither ROR-γt 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-γt expression.