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

A paper in Nature Immunology describes a new subset of fibroblastic reticular cells, defined by expression of Gremlin 1, in lymphoid tissues that maintain homeostasis of conventional dendritic cells and ensure proper T cell immunity.

Gremlin neighbours for DCs

Babies have a hard time of it — not only do they have a bit of a struggle coming into the world, but also they are then particularly susceptible to various infections with viruses and bacteria. It is generally believed that neonatal susceptibility to infection is due to a developmental defect in immune function, particularly a delay in the maturation of effective T helper 1 (T H 1)-cell responses. But, little is known about how neonatal CD8 T cells respond to virus infection. Now, Marchant and colleagues show that neonates can generate a mature and functional CD8 T-cell response to infection with human cytomegalovirus (HCMV), which might have implications for the development of neonatal vaccines. Marchant and colleagues studied the functional capability of CD8 T cells in congenitally infected neonates. Fetal T cells at the 28-week stage showed characteristics of early differentiated cells, with numerous highly activated cells undergoing proliferation. Infected newborns had higher proportions of activated CD8 T cells than uninfected neonates, and repertoire analysis showed that HCMV infection had triggered the oligoclonal expansion of CD8 T cells. Analysis of expression markers showed that the T cells of newborns had the characteristics of antigen-experienced cells with a phenotype resembling that of memory cells. Intracellular staining of these T cells showed high levels of perforin and granzyme A, and the T cells had perforindependent cytolytic activity. The T cells were also able to produce antiviral cytokines, such as interferon-γ. So, fetal and neonatal CD8 T cells do seem to be able to respond to virus infections. These results indicate that there might be fewer developmental constraints on the CD8 T-cell compartment than on CD4 T cells, and although further work on the mechanisms of T-cell priming in neonates is necessary, it might be possible to develop neonatal vaccination for virus infections. Elaine Bell References and links ORIGINAL RESEARCH PAPER Marchant, A. et al. Mature CD8+ T lymphocyte response to viral infection during fetal life. J. Clin. Invest. 111, 1747–1755 (2003)

HIV: Under pressure

NATURE REVIEWS | IMMUNOLOGY VOLUME 5 | JANUARY 2005 | 7 A recent report in Nature describes a new biological function for mast cells: limiting the toxicity and pathology associated with endothelin-1 (ET1). ET1 is a 21-amino-acid peptide with potent vasoconstrictor activity, and it is released by vascular endothelial cells during sepsis and other pathological processes, such as asthma and atherosclerosis. Previous in vitro studies have shown that ET1 induces the activation of mast cells, which triggers the release of proteases that degrade it; however, the involvement of mast cells in the regulation of ET1-associated pathology in vivo is unknown. So, to assess their role in ET1-induced pathology, Maurer et al. gave an intraperitoneal injection of ET1 to wild-type and mast-cell-deficient mice. All mast-celldeficient mice developed severe hypothermia and diarrhoea, and most died within 3 hours of the injection. By contrast, ET1 injection had no effect on wild-type mice. Restoration of mast cells to the peritoneal cavity of the mutant mice, by adoptive transfer of wild-type mast cells, completely protected the mice from ET1-induced morbidity and mortality. Using an inhibitor of mast-cell degranulation, BAPTA-AM, the authors next assessed whether degranulation is required for the reduction of ET1-induced toxicity in vivo. When wild-type cells were treated with BAPTA-AM before transfer to mast-cell-deficient mice, the protective effect of the transferred cells was greatly reduced. Further studies identified that chymase, which is released on mast-cell degranulation, is involved in mediating the protective effect by degrading ET1, as wild-type mice that were pretreated with a chymase inhibitor developed hypothermia and diarrhoea after injection of ET1 and had increased amounts of ET1 in the peritoneal cavity compared with untreated mice. To further explore the mechanism of ET1induced mast-cell activation, the authors tested the ability of ET1-receptor antagonists to alter the susceptibility of wild-type mice to ET1induced pathology. Wild-type mice pretreated with an antagonist selective for the ET1 receptor ET A and then injected with ET1 developed marked hypothermia and diarrhoea, although not to the extent seen in mast-cell-deficient mice, indicating that ET A has an important role in mediating mast-cell activation. Accordingly, mast-cell-deficient mice that were reconstituted with mast cells that lack expression of ET A were not protected from ET1-induced hypothermia and diarrhoea, and some mice died. Moreover, in the peritoneal cavity of these mice, mast-cell degranulation was reduced, and ET1 levels were increased compared with those of mice that were reconstituted with wild-type cells, indicating that mast cells limit ET1-associated pathology in vivo by reducing the concentration of the peptide. Finally, the authors used the caecal ligation and puncture (CLP) model of acute bacterial peritonitis to assess the biological significance of mast-cell-mediated protection from ET1induced pathology. As expected, the mortality that occurred within 90 hours of CLP was greater in mast-cell-deficient mice than in wild-type mice. However, reconstitution of mast-cell-deficient mice with wild-type cells, but not with ET A deficient cells, increased their survival to levels that were similar to those of wild-type mice, indicating that protective mast-cell function in the CLP model involves ET1and ET A -dependent mechanisms. In this study, the authors describe a novel role for mast cells in tempering the toxicity that is induced by endogenous mediators, and they speculate that, in future, mast-cell-dependent mechanisms might also be found to regulate the toxicity of other compounds. Lucy Bird References and links ORIGINAL RESEARCH PAPER Maurer, M. et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432, 512–516 (2004). Tempering toxicity M A S T C E L L S barrier in wild-type and Tlr3 mice: after infection with WNV or stimulation with the viral mimic poly I:C (polyinosinic–polycytidylic acid), permeability was increased in wild-type mice but not in Tlr3 mice. A further insight into the pathogenesis of severe disease was provided by results indicating that signalling through tumour-necrosisfactor receptor 1 downstream of TLR3 promotes WNV entry to the brain. Sporadic outbreaks of WNV infection of humans have become increasingly common in the past five years, particularly in North America and Europe. This new work identifying TLR3 as the receptor that allows WNV to enter the brain can hopefully be exploited for the development of new therapeutics. Sheilagh Molloy, Associate Editor, Nature Reviews Microbiology

Lucy Bird

Papers

Gremlin neighbours for DCs

HIV: Under pressure

Mast cells: Tempering toxicity

Lipids and stress — a deadly duo.

Pulling out the stops