Details

Autor(en) / Beteiligte

• Dose, Marei
• Sleckman, Barry P
• Han, Jin
• Bredemeyer, Andrea L
• Bendelac, Albert
• Gounari, Fotini

Titel

Intrathymic proliferation wave essential for Vα14⁺ natural killer T cell development depends on c-Myc

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-05, Vol.106 (21), p.8641-8646

Ort / Verlag

National Academy of Sciences

Erscheinungsjahr

2009

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The molecular requirements for invariant Vα14-bearing natural killer T cells (iNKT) in the thymus are poorly understood. A minute population of [almost equal to]500 newly selected CD69⁺CD24⁺ stage 0 (ST0) iNKT cells gives rise to [almost equal to]100 times more CD44neg/loCD24⁻ stage 1 (ST1) cells, which then generate similar frequencies of CD44hiCD24⁻ stage 2 (ST2) and mature iNKT cells. Although the increased number of ST1 compared with ST0 cells indicates the initiation of a proliferation wave in the very early stages of iNKT cell development, details about the controlling mechanism are currently lacking. Here, we show that the transcription factor c-Myc is required for iNKT cell development. Conditional ablation of c-Myc in double-positive thymocytes specifically impacted iNKT but not conventional T cell development. Within the iNKT population, a progressive reduction of iNKT cells was observed starting at ST1 ([almost equal to]50-fold) and ST2 ([almost equal to]350-fold), with a complete lack of mature cells in thymus, spleen, and liver. ST0/ST1 c-Myc-deficient iNKT cells showed reduced proliferation. In contrast, annexin V staining did not reveal increased apoptosis, and transgenic overexpression of BCL-2 did not rescue iNKT cell development in c-Myc-deficient mice. Moreover, expression of known iNKT differentiation factors such as Plzf and Gata3 was not dramatically altered. These, findings provide compelling evidence that c-Myc mediates an intrathymic proliferation wave immediately after agonist selection of iNKT cells and illustrate the importance of this expansion for the generation of mature iNKT cells in vivo.