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Selective Requirement for c-Myc at an Early Stage of V14i NKT Cell Development ¹

Marcin P. Mycko^2,*, Isabel Ferrero^*, Anne Wilson^*, Wei Jiang^*, Teresa Bianchi^3,*, Andreas Trumpp^4, and H. Robson MacDonald^5,*

^* Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; Ecole Polytechnique Fédérale de Lausanne, ISREC-Swiss Institute for Experimental Cancer Research, School of Life Science, Epalinges, Switzerland

V14 invariant (V14i) 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⁺ V14i 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 V14i 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 V14i NKT cell development without perturbing the development of conventional T cells. In the absence of c-Myc, V14i NKT cell precursors are blocked at an immature CD44^lowNK1.1^– stage in a cell autonomous fashion. Residual c-Myc-deficient immature V14i NKT cells appear to proliferate normally, cannot be rescued by transgenic expression of BCL-2, and exhibit characteristic features of immature V14i 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 V14i NKT cell development to promote progression beyond the CD44^lowNK1.1^– precursor stage.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants to H.R.M from the Swiss National Science Foundation (3100A-120165) and to A.T. from the Swiss National Science Foundation (3100A0-116553) and the Swiss Cancer League (OCS-01863--02-2006). M.P.M was a recipient of an European Federation of Neurological Societies Fellowship.

² Current address: Medical University of Lodz, 90-153 Lodz, Poland.

³ Current address: Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115.

⁴ Current address; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

⁵ Address correspondence and reprint requests to Dr. H. Robson MacDonald, Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland. E-mail address: hughrobson.macdonald{at}licr.unil.ch

⁶ Abbreviations used in this paper: V14i, V14 invariant; DP, CD4⁺CD8^+; PLZF, promyelocytic leukemia zinc finger; SLAM, signaling lymphocytic activation molecule; SAP, SLAM-associated protein; DN, CD4^–CD8^–; SP, single positive; Treg, regulatory T cell; TBP, TATA-binding protein; GalCer, -galactosylceramide; ic, intracellular; BM, bone marrow; 7AAD, 7-aminoactinomycin D.