Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.

/pdf/t-cell-metabolism-drives-immunity-3hm75bf0o2.pdf

T cell metabolism drives immunity

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

Recent evidence indicates that mitochondria lie at the heart of immunity. Mitochondrial DNA acts as a danger-associated molecular pattern (DAMP), and the mitochondrial outer membrane is a platform for signaling molecules such as MAVS in RIG-I signaling, and for the NLRP3 inflammasome. Mitochondrial biogenesis, fusion and fission have roles in aspects of immune-cell activation. Most important, Krebs cycle intermediates such as succinate, fumarate and citrate engage in processes related to immunity and inflammation, in both innate and adaptive immune cells. These discoveries are revealing mitochondrial targets that could potentially be exploited for therapeutic gain in inflammation and cancer.

Mitochondria are the powerhouses of immunity.

Transcription factors define tissue T cells The immune system fights microbial invaders by maintaining multiple lines of defense. For instance, specialized memory T cells [resident memory T cells (Trms)] colonize portals of pathogen entry, such as the skin, lung, and gut, to quickly halt reinfections. Mackay et al. now report that in mice, Trms as well as other tissue-dwelling lymphocyte populations such as natural killer cells share a common transcriptional program driven by the related transcription factors Hobit and Blimp1. Tissue residency and retention of lymphocytes require expression of Hobit and Blimp1, which, among other functions, suppress genes that promote tissue exit. Science, this issue p. 459 Tissue-dwelling lymphocyte populations share a common transcriptional signature. Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.

Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes

/pdf/relief-for-tired-t-cells-1hkr5nisw3.pdf

Relief for tired T cells

Plasmacytoid dendritic cells: Division of labour

lipopolysaccharide (LPS) can be lethal, there are numerous regulatory mechanisms in place to limit its toxic effects. Now, Luke O’Neill and colleagues identify a new pathway that dampens LPS-induced inflammatory responses, involving microRNAmediated downregulation of the proinflammatory protein programmed cell death 4 (PDCD4). In line with previous studies showing that mice deficient in PDCD4 are resistant to the induction of experimental inflammatory diseases, the authors found that PDCD4-deficient mice were less susceptible to LPS-induced death than wild-type mice. Further investigation revealed that PDCD4 expression is modulated following ligation of Tolllike receptor 4 (TLR4) by LPS. LPS stimulation of a macrophage cell line (RAW264.7) or human peripheral blood mononuclear cells first led to a slight increase in PDCD4 expression (after 1 hour) and then to a substantial decrease after 8 and 24 hours. The delayed decrease in PDCD4 expression following LPS stimulation coincided with increased production of the anti-inflammatory cytokine interleukin-10 (IL-10). The known function of PDCD4 as a translational inhibitor is consistent with the finding that LPS-treated PDCD4deficient cells contained less Il10 mRNA but more IL-10 protein, indicating that the regulation of IL-10 by PDCD4 is at the translational level. In addition, low PDCD4 expression (achieved using Pdcd4-specific small interfering RNA) was associated with less activation of nuclear factor-κB and downstream Il6 transcription after LPS treatment, an effect that is suggested to be secondary to the translation inhibitory function of PDCD4. So how is PDCD4 expression downregulated? Previous studies have reported that Pdcd4 mRNA is targeted by the microRNA miR-21, preventing production of PDCD4 protein. Accordingly, the authors found that 4 hours after LPS treatment miR-21 expression was induced, with a tenfold increase detected after 18 hours. This induction of miR-21 expression was dependent on intact TLR signalling capacity. A role for miR-21 expression in the regulation of PDCD4 was consistent with the finding that pre-treatment of RAW264.7 cells with antisense oligonucleotides specific for miR-21, but not control antisense RNA, blocked the LPS-induced decrease in PDCD4 expression. Similarly, a morpholino oligonucleotide designed to block the miR-21binding site of Pdcd4 abrogated LPS-induced PDCD4 downregulation, confirming that LPS regulates the translation of Pdcd4 mRNA through the induction of miR-21. PDCD4 was also found to be regulated at the protein level through ubiquitylation and degradation by the proteasome, as pre-treatment of RAW264.7 cells with a proteasome inhibitor also blocked the LPS-induced decrease in PDCD4 protein levels after 6 hours. Finally, the authors confirmed the link between LPS-induced miR-21 induction, PDCD4 downregulation and increased IL-10 by showing that transfection of RAW264.7 cells with pro-miR-21 (the precursor of mature miR-21) resulted in higher IL-10 production after LPS treatment. This did not occur in PDCD4-deficient cells, confirming that the effect of pro-miR-21 was specifically due to the targeting of Pdcd4 mRNA. This newly described role for miR-21 as a negative regulator of inflammation opens up new avenues for therapeutic manipulation of TLR4 activation during sepsis and inflammatory diseases. Lucy Bird

Innate immunity: MicroRNAs limit LPS lethality

Mucosal immunology: Setting up camp

/pdf/macrophages-yo-yo-during-weight-loss-3ojv2p0dtk.pdf

Lucy Bird

Papers

Relief for tired T cells

Plasmacytoid dendritic cells: Division of labour

Innate immunity: MicroRNAs limit LPS lethality

Mucosal immunology: Setting up camp

Macrophages yo-yo during weight loss.