5 C). marrow chimeras suggests that miR-150 differentially controls the development of NK and iNKT cell lineages by targeting c-Myb. The innate immune system provides early host defense against viruses, bacteria, and tumor cells. Two of its cell lineages, NK and invariant NK T (iNKT) cells, do not ZPK require prior sensitization for effector function and play critical roles in both initially fighting infection and subsequently activating the adaptive immune response. NK cells develop in the BM and share a common lymphoid progenitor with NMDA T and B cells (Kondo et al., 1997). The committed NK cell precursors (NKPs) express the shared IL-2 and IL-15 receptor common subunit (CD122;Rosmaraki et al., 2001). NK cell development is critically dependent on IL-15, as mice lacking IL-15 or any component of its receptor or signaling have a block in NK cell differentiation in the BM (DiSanto et al., 1995;Suzuki et al., 1997;Kennedy et al., 2000;Gilmour et al., 2001;Vosshenrich et al., 2005). As NK cells mature, they sequentially acquire the cell surface receptors NK1.1 (in C57BL/6 mice), CD94-NKG2A, Ly49 receptors, and the 2-integrin CD49b (DX5;Hesslein and Lanier, 2011). Terminal maturation is accompanied by loss of CD27 expression and up-regulation of CD11b expression, together with optimal cytolytic function and IFN- production. NK cell specificity is fine-tuned by stochastic expression of activating and inhibitory receptors of the Ly49 family. Some activating Ly49 members can detect specific virus-encoded products (e.g., Ly49H recognizes the mouse cytomegalovirus m157 glycoprotein;Arase et al., 2002;Smith et al., 2002). Individual inhibitory Ly49 members recognize distinct MHC class I allotypes (e.g., Ly49C recognizes H2bin C57BL/6 mice) and are important in self-recognition, whereas other NMDA inhibitory Ly49 genes produce receptors that do not recognize the autologous MHC class I (e.g., Ly49A in C57BL/6 NMDA mice;Orr and Lanier, 2011). NKT cells share properties with both NK cells and T cells in that they express receptors of the NK cell lineage, including NK1.1 and members of the Ly49 family, along with a TCR. The majority of NKT cells express an invariant TCR (V14J18 in mice) that pairs with a limited repertoire of TCR chains (V8, V7, or V2 in mice;Godfrey et al., 2010). These NKT cells, also referred to as iNKT cells, can be identified using CD1d tetramers loaded NMDA with the glycosphingolipid antigen -galactosylceramide (Matsuda et al., 2000). iNKT cells develop from CD4+CD8+double-positive V14J18 TCR+thymic precursors (Godfrey et al., 2010). After positive selection, iNKT-cell precursors down-regulate their expression of CD24 (HSA), and transition through several maturation stages accompanied by the expression of NK1.1, CD44, and CD122. After CD122 up-regulation, iNKT cells proliferate in response to IL-15 and migrate from the thymus to the periphery, where they are most abundant in the spleen, liver, and BM. Although much has been learned about the transcriptional regulation of NK and iNKT lineage development (Godfrey et al., 2010;Hesslein and Lanier, 2011), less is known about the posttranscriptional mechanisms that regulate NK and iNKT cells. microRNAs (miRNAs) are noncoding RNAs, expressed from endogenous genes, which act on protein-encoding mRNAs, targeting them for translational repression or degradation (Bartel, 2004). Many miRNAs are expressed in a stage- and cell-specific fashion in the hematopoietic system (Kuchen et al., 2010), and emerging evidence suggests that they regulate lymphocyte differentiation and function (Muljo et al., 2005;Cobb et al., 2006;Koralov et al., 2008;X. Zhou et al., 2008;Liston et al., 2008;Zhou et al., 2009;Fedeli et al., 2009). Deletion of the miRNA-processing enzymes Dicer or Dgcr8 leads to defects in NK cell activation, survival, and function during mouse cytomegalovirus infection (Bezman et al., 2010). In addition, loss of miRNAs in the BM or thymus leads to impaired iNKT cell development and function (Fedeli et al., 2009;Zhou et al., 2009;Seo et al., 2010). These results, and the description of a subset of miRNAs differentially expressed in NK and iNKT versus other hematopoietic cells (Fedeli et al., 2009;Bezman et al., 2010;Kuchen et al., 2010), raise a question as to how individual miRNAs present in high amounts in.