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Proc Natl Acad Sci U S A. 2009 May 26;106(21):8641-6. doi: 10.1073/pnas.0812255106. Epub 2009 May 7.

Intrathymic proliferation wave essential for Valpha14+ natural killer T cell development depends on c-Myc.

Author information

1
Committee on Immunology, Department of Medicine, Rheumatology, University of Chicago, Chicago, IL 60637, USA.

Abstract

The molecular requirements for invariant Valpha14-bearing natural killer T cells (iNKT) in the thymus are poorly understood. A minute population of approximately 500 newly selected CD69(+)CD24(+) stage 0 (ST0) iNKT cells gives rise to approximately 100 times more CD44(neg/lo)CD24(-) stage 1 (ST1) cells, which then generate similar frequencies of CD44(hi)CD24(-) 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 (approximately 50-fold) and ST2 (approximately 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.

PMID:
19423665
PMCID:
PMC2689024
DOI:
10.1073/pnas.0812255106
[Indexed for MEDLINE]
Free PMC Article

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