In contrast to peptide-recognizing T cells, invariant natural killer T (iNKT)

In contrast to peptide-recognizing T cells, invariant natural killer T (iNKT) cells express a semi-invariant T cell receptor that specifically recognizes self- or foreign-lipids presented by CD1d molecules. iNKT cells development. Upregulated after TCR activation, Jarid2 directly binds to the PLZF promotor like a transcriptional repressor. Therefore, deficiency of Jarid2 led to significant growth of PLZFhigh NKT2 cells (51). In addition, the transcriptional repressor NKAP was shown to be required for the development of iNKT cells, as the iNKT development was completely abrogated at stage 0 in mice deficient of NKAP (CD4-Cre??NKAPflox/flox) (52). How NKAP regulates iNKT cell development is not obvious, but its connection with the histone deacetylase 3 (Hdac3) may be important, as NKAP is known to associate with Hdac3 and a similar defect of iNKT cells was observed in Hdac 3 conditional knockout mice (CD4-Cre??Hdac3flox/flox) (53). A recent report demonstrated the H3K27me3 histone demethylase UTX ABT-263 inhibition is essential for iNKT cell development, especially the differentiation of NKT1 cells, as there was substantially fewer T-bet+ NKT1 cells in UTX-deficient mice while NKT2 and NKT17 cells were not affected (54). UTX not only directly binds to the promoters of T-bet and CD122 genes but also influences the epigenetic scenery and transcription of PLZF-activated genes (54). MicroRNAs (miRNAs) MicroRNAs are small noncoding single-strand RNAs (~22?nt) that modulate the stability and transcriptional activities of messenger RNAs (mRNAs) and this mechanism influence the transcriptomes of various cells, leading to further effects on cellular proliferation, apoptosis, lineage commitment, and differentiation (55). Perhaps not surprisingly, complete loss of mature iNKT cells was observed in mice lacking Dicer (CD4-Cre??Dicerflox/flox), which are incapable of generating functional miRNAs in T cells, as a result demonstrating that miRNAs are essential for the development of iNKT cells (56). miR-181a is definitely abundant in DP thymocytes and could augment TCR signaling strength enhancing the basal activation of TCR signaling molecules, such as improved basal phosphorylation level of Lck and ERK (57). Deletion of miR-181a (miR-181a/b-1?/? mice) completely clogged iNKT cell development in the DP/Stage 0, which was presumably due to reduced responsiveness to TCR signals as exogenous agonistic ligand (GalCer) could ABT-263 inhibition save iNKT cell generation (58). The miR-17C92 family cluster is also crucial for the development of Rabbit Polyclonal to UBE1L iNKT cells, in that absence of miRNAs of the miR-17C92 family cluster (triple knockout of three paralogs miR-17C92, miR-106aC363, and miR-106bC25 clusters) resulted in almost total ablation of the three iNKT effector subsets (59). Excessive TGF- signaling was seen in the remaining triple knockout iNKT cells, but it did not solely account for the impaired iNKT cell development, because deletion of TGF-RII did not fully restore the hemostasis of iNKT cells (59). It was further found that the Let-7 family miRNAs, probably the most abundant family of miRNAs in mammals, tightly settings the differentiation of iNKT subsets (60, 61). Let-7 miRNAs are abundant in NKT1 cells while low in NKT2 and NKT17 cells, focusing on mRNAs and inhibiting PLZF manifestation, consequently, directing iNKT cell differentiation into PLZFlow NKT1 lineage (61). Moreover, Lin28 inversely regulates Let-7 miRNAs, and Lin28 transgenic mice, which are practically deficient in Let-7 miRNAs, showed significantly improved NKT2 and NKT17 cells (61). miR-150 is definitely indicated in lymphocytes (B, T, and NK cells) and has been implicated in their maturation. Correspondingly, miR-150 manifestation is definitely indicated in iNKT cells after stage 0 (62, 63). Inside a combined bone marrow chimera system, cell-intrinsic deficiency of miR-150 mildly affected iNKT cell development (62, 63), while overexpression of miR-150 considerably clogged maturation of iNKT cells beyond stage 0 (62). This suggests that fine-tuning of miR-150 level might be critical ABT-263 inhibition for iNKT cell development. Though the molecular pathway underlying this miR-150-dependent iNKT cell development is definitely unclear, rules of c-Myb by miR-150 could be involved (62, 63). Cellular Protein Degradation System While playing a central part in iNKT cell development, PLZF is definitely in the beginning induced in the stage 0 iNKT cells, and its manifestation can be controlled from the transcription element Runx1 through direct binding to a critical enhancer of PLZF gene (64). Using Chip-Seq analysis,.