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.

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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

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Immune regulation: Cellular collaborations

Retinoic acid promotes secondary lymphoid organ formation during embryogenesis to establish adult immunity.

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Development: we are what mum eats!

The parasite Schistosoma mansoni causes chronic infections in humans, because it can evade host immune defences long-term. Such infections alter the immune response in a manner that prevents the development of various immune-mediated diseases, indicating that molecules produced by schistosomes might be useful as immunomodulatory therapeutic agents. Now, a paper published in The Journal of Experimental Medicine shows that S. mansoni eggs secrete a protein that binds certain chemokines, and administration of this protein inhibits inflammation in several animal models of disease. Because certain viruses have been shown to produce chemokinebinding proteins (CKBPs) and because infection with S. mansoni affects the local recruitment of immune cells, Philip Smith and colleagues examined whether S. mansoni produces CKBPs. Secretions from live eggs (produced by adult worms, which reside in the intestinal blood vessels of infected individuals) were shown to bind the chemokines CXC-chemokine ligand 8 (CXCL8; also known as IL-8) and CC-chemokine ligand 3 (CCL3). A single protein was found to provide this activity, and the gene that encodes this protein was cloned. A recombinant form of this novel CKBP was then shown not only to bind specific chemokines but also to prevent these chemokines from interacting with their receptors, thereby inhibiting the migration and activation of leukocytes that express the cognate chemokine receptors (particularly neutrophils, but also macrophages and eosinophils). This is the first report of a human pathogen that produces a CKBP. The authors suggest that, because of its potent anti-inflammatory activity, S. mansoni CKBP has potential as a treatment for acute inflammation. This is supported by data from three in vivo models of acute inflammation that show that intravenous administration of recombinant S. mansoni CKBP suppresses leukocyte infiltration. Davina Dadley-Moore

Lucy Bird

Papers

Immune regulation: Cellular collaborations

Development: we are what mum eats!

TLRs are crucial for B cells too

Autoimmunity: Benefits of blocking the immunoproteasome

T cells: Helper cell metamorphosis