Article: article from journal or magazin.
Selective requirement for c-Myc at an early stage of V(alpha)14i NKT cell development.
Journal of immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Valpha14 invariant (Valpha14i) NKT cells are a subset of regulatory T cells that utilize a semi-invariant TCR to recognize glycolipids associated with monomorphic CD1d molecules. During development in the thymus, CD4(+)CD8(+) Valpha14i NKT precursors recognizing endogenous CD1d-associated glycolipids on other CD4(+)CD8(+) thymocytes are selected to undergo a maturation program involving sequential expression of CD44 and NK-related markers such as NK1.1. The molecular requirements for Valpha14i NKT cell maturation, particularly at early developmental stages, remain poorly understood. In this study, we show that CD4-Cre-mediated T cell-specific inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biological activities, selectively impairs Valpha14i NKT cell development without perturbing the development of conventional T cells. In the absence of c-Myc, Valpha14i NKT cell precursors are blocked at an immature CD44(low)NK1.1(-) stage in a cell autonomous fashion. Residual c-Myc-deficient immature Valpha14i NKT cells appear to proliferate normally, cannot be rescued by transgenic expression of BCL-2, and exhibit characteristic features of immature Valpha14i NKT cells such as high levels of preformed IL-4 mRNA and the transcription factor promyelocytic leukemia zinc finger. Collectively our data identify c-Myc as a critical transcription factor that selectively acts early in Valpha14i NKT cell development to promote progression beyond the CD44(low)NK1.1(-) precursor stage.
Animals, CD8-Positive T-Lymphocytes/immunology, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Gene Expression Regulation/immunology, Haplotypes/immunology, Immunologic Memory/immunology, Interleukin-4/genetics, Interleukin-4/immunology, Mice, Mice, Transgenic, Natural Killer T-Cells/cytology, Natural Killer T-Cells/immunology, Phenotype, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/metabolism, RNA, Messenger/genetics, Receptors, Antigen, T-Cell, alpha-beta/immunology, Time Factors
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