miR-142 keeps CD4+ DCs in balance.

miR-142 keeps CD4 DCs in balance ---------------------------------------------------------------------------------------------------------------Gabrielle T. Belz1 1THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH In this issue of Blood, Mildner et al report elucidation of a transcriptome-wide miRNA map for in vivo mononuclear phagocyte populations. Using this approach, they identify that the miRNA miR-142 was critical for dendritic cell (DC) development, particularly for homeostasic regulation of the CD4 DC subset.1 Dendritic cells (DCs) are a rare type of white blood cell that play a critical role in bridging the innate and adaptive immune system. They are essential for presentation of both endogenous (self-) antigens and foreign (pathogen-derived) antigens and as such constitute a frontline defense against microorganisms. To effectively provide immune protection, different DC subsets have evolved. The genetic program that coordinates the development of these subsets is controlled largely by cytokines and transcription factors.2 Interferon regulatory factors (Irf), namely Irf4 and Irf8, are essential for the development of CD4 and CD8 DC lineages, respectively, in mice, and PU.1 is a pioneering transcription factor for myeloid cell development (see figure). While the fundamental differentiation program for DCs is laid down by specific transcription factors, increasingly it is recognized that fine-tuning of this program is likely to depend on an added layer of control mediated through microRNA (miRNA) expression.3,4 MicroRNAs are a class of small noncoding RNAs that repress translation of target genes through their complementary binding to the 3 untranslated regions of mRNAs by repressing translation initiation, induction of transcript decapping and deadenylation, and degradation of the mRNA. Canonical miRNAs are initially transcribed as long primary transcripts that are then processed into mature 20-24 nucleotide (nt)–long miRNAs. In mammals, posttranscriptional modulation of gene expression depends on an imperfect matching between the miRNA and target. However, perfect complementarity between the 5 proximal seed sequence of the miRNA with the mRNA target is thought to be particularly important in metazoans. This feature introduces a level of promiscuity in which each miRNA can bind multiple targets (hundreds to thousands) and reciprocally, each mRNA can be targeted by many different miRNAs. Some understanding of miRNA expression in DCs has been gained through investigation mainly of in vitro GM-CSF– derived DCs. This has resulted in identification of several miRNAs, mainly in human cultured DCs, that target cytokine production (miR-10a, miR-21, miR-142-3p), DC activation (miR-155 and miR146), and antigen presentation (miR-511, miR-99b, miR-211). Understanding miRNA expression and requirements in different in vivo DC subsets, and which components of the differentiation and maturation pathways they target, has been a significant challenge. Deletion of the gene encoding Dicer, a key enzyme necessary for the biogenesis of miRNAs, specifically in CD11c cells, resulted in only a minimal impact on DC differentiation.4 These mice displayed a perturbed Langerhans cell compartment, but conventional DCs were relatively normal. The lack of phenotype observed in the conventional DC compartment may have been due to the fact that miRNAs are very stable. Combined with the quite short half-life of DCs, this is likely to result in insufficient time for the miRNAs to be efficiently depleted in mature cells. Thus, to fully evaluate the involvement of miRNAs in DC approaches to deplete miRNAs from earlier stages of differentiation will be important. Potential model of the interactions between miR-142 and key transcription factors implicated in the pathway. At steady-state (top panel), the interplay between PU.1, Irf8, and Irf4 orchestrates the differentiation of CD4 and CD8 DCs. Heterodimeric binding of PU.1 and Irf8 induces expression of the MHC class II transactivator CIITA, which may be repressed by transcription factors such as Blimp1 to allow efficient induction of DC antigen presentation required for T-cell priming. Modulation of the PU.1/Irf4 complex by miR-142 (bottom panel) disrupts the generation of CD4 DCs and favors the generation of CD8 DCs. Because Irf4 is important for induction of other transcription factors including Blimp1, failure of CIITA repression leads to elevated DC activation and maturation and impaired CD4 T-cell priming ability. miR-142 may thus regulate the balance of different transcription factors to guide the outcome of an immune response.