The transcription factor PLZF (Zbtb16) directs the effector program of the NKT cell lineage Adam K. Savage 1 , Michael G. Constantinides 1 , Jin Han 1 , Damien Picard 1 , Emmanuel Martin 2 , Bofeng Li 3 , Olivier Lantz 2 , and Albert Bendelac 1 1Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA 2Laboratoire d'Immunologie et Unité INSERM 653, Institut Curie, Paris, 75005 France 3Committee on Immunology, Department of Medicine, Pathology and Pediatrics, University of Chicago, Chicago, IL 60637, USA Summary The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger; Zbtb16), a member of the BTB/POZ-ZF family of transcription factors which includes the CD4 lineage-specific c-Krox (Th-POK, Zbtb7b), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naïve phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4 thymocytes to acquire effector differentiation and migrate to non-lymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development. Introduction The development of thymic αȕ cell lineages relies on signaling processes that are initiated upon TCR engagement by MHC or MHC-like ligands at the CD4 + CD8 + double positive (DP) stage (reviewed in (He and Kappes, 2006; Singer and Bosselut, 2004)). Although overlapping with their positive selection, the lineage commitment of thymocytes can be separated and manipulated based on the expression of signature components of transcriptional networks involved in lineage decisions. For example, the antagonistic expression and function of c-Krox (Th-POK, Zbtb7b) and Runx3 define the CD4 and CD8 lineages, respectively (He et al., 2005; Setoguchi et al., 2008; Sun et al., 2005; Wildt et al., 2007). A fraction of MHC class-II restricted CD4 T cells further differentiates into CD25 + regulatory T cells characterized by the transcription factor Foxp3 (Fontenot et al., 2003; Hori et al., 2003). Little is known, however, about the transcriptional regulation of unconventional αȕ T cell lineages such as NKT cells, MAIT cells or CD8αα intraepithelial lymphocytes (reviewed in (Bendelac et al., 2007; Matsuda and Gapin, 2005; Shires et al., 2001; Treiner and Lantz, Corresponding author: abendela@bsd.uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Published as: Immunity. 2008 September ; 29(3): 391–403. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript