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

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

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular requirements for invariant Vα14-bearing natural killer T cells (iNKT) in the thymus are poorly understood. A minute population of ≈500 newly selected CD69+CD24+ stage 0 (ST0) iNKT cells gives rise to ≈100 times more CD44neg/loCD24- stage 1 (ST1) cells, which then generate similar frequencies of CD44 hiCD24- 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 (≈50-fold) and ST2 (≈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.

Original languageEnglish (US)
Pages (from-to)8641-8646
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number21
DOIs
StatePublished - May 26 2009

Keywords

  • Cell cycle
  • iNKT cells
  • Nonconventional lymphocytes

ASJC Scopus subject areas

  • General

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