title: Selective requirement for c-Myc at an early stage of V(alpha)14i NKT cell development.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Mycko
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.forename: Anne
authors.initials: A
authors.lastname: Wilson
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Teresa
authors.initials: T
authors.lastname: Bianchi
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald