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

930 | DECEMBER 2004 | VOLUME 4 www.nature.com/reviews/immunol morbidity at high doses, indicating that lipocalin-2 has an important role in innate defence against bacterial infection. In the serum, the concentration of free iron is tightly regulated by ironbinding proteins such as transferrin, so invading pathogens must acquire iron by secreting siderophores, which effectively compete for iron. The authors have previously shown that lipocalin-2 can bind catecholatetype siderophores (such as enterochelin) but not other types of siderophore (such as ferrichrome). As E. coli strain H9049 depends on enterochelin for importing iron, its growth was inhibited when cultured in acutephase serum from wild-type mice but not from lipocalin-2-deficient mice. By contrast, the in vitro growth of Staphylococcus aureus, which does not depend on enterochelin, was not affected by the presence of lipocalin-2. The specificity of the protective effect of lipocalin-2 against enterochelin-dependent bacterial infection was then examined in vivo. Mice were challenged with E. coli either with or without coinjection of ferrichrome, which allows bacteria to acquire iron in an enterochelin-independent manner. Similar to lipocalin-2deficient mice, wild-type mice that received bacteria and ferrichrome showed markedly increased morbidity, indicating that lipocalin-2 confers resistance to bacterial infection by abrogating enterochelin-dependent iron uptake by bacteria.

Innate immunity: The fight for iron

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Immune evasion: Virus 2 — dendritic cell 0

well-known role in T-cell development, was recently found to be required for enabling immature B cells to become marginal zone (MZ) B cells — an innate-like population of mature B cells that resides in the spleen and is crucial for host defence against blood-borne bacteria. Specifically, Notch2 signalling induced by Delta-like ligand 1 (DLL1) drives the development of transitional 1 (T1) B cells into MZ B cells (via a MZ B-cell precursor) rather than into follicular B cells. However, it was unclear which cells in the spleen express DLL1 and how MZ B-cell development is regulated. Now, Guidos and colleagues show that DLL1 expression by vascular endothelial cells in the MZ and red pulp of the mouse spleen provides a niche to promote MZ B-cell development and that the DLL1–Notch2 interaction is positively regulated by the Fringe family glycosyltransferases. Flow cytometry analysis of splenic B cells from Notch2 reporter mice indicated that the highest levels of Notch2 are present in MZ B-cell precursors and MZ B cells. In addition, histological analysis of whole spleens revealed that DLL1 (as indicated by the expression of a LacZ reporter) was mainly observed in the red pulp vasculature, in particular in endothelial cells that interact closely with lymphocytes in the vessel lumen, and was the only Notch ligand to be highly expressed in the MZ. In contrast to previous predictions, expression of the DLL1–LacZ reporter was not detected in haemato poietic cells, including splenic dendritic cells. Experiments with chimeric mice confirmed that the expression of DLL1 by radioresistant stromal cells is required to support MZ B-cell development. Next, the authors investigated whether Notch2-dependent MZ B-cell development was influenced by the Fringe enzymes Lunatic Fringe and Manic Fringe, which are thought to enhance interactions of Notch proteins with their ligands by modifying Notch glycosylation. Again, by generating various chimeric animals, they showed that deficiency of either Fringe enzyme alone in transferred precursor cells compromised MZ B-cell development in mixed chimeras, but deficiency of both enzymes led to a more significant reduction in MZ B-cell development. This suggests that Lunatic Fringe and Manic Fringe function cooperatively to promote Notch2-mediated MZ B-cell development and that, in the absence of Fringe proteins, the DLL1–Notch2 interaction is inherently weak. So, the authors propose that the vasculature of the red pulp provides a microenvironmental niche in which MZ B-cell precursors compete for limited amounts of DLL1, allowing some to mature into MZ B cells. Modification of Notch2 by the Fringe enzymes enhances this competition for DLL1 and thereby regulates the size of the MZ B-cell pool. Lucy Bird

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B-cell development: Fringe benefits

Blind mole rats are resistant to cancer. A new study describes how activation of transposons triggers an innate immune response that eliminates premalignant cells.

The mole rat's secret to cancer resistance.

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Lucy Bird

Papers

Innate immunity: The fight for iron

Immune evasion: Virus 2 — dendritic cell 0

B-cell development: Fringe benefits

The mole rat's secret to cancer resistance.

Selecting skin T cells