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

VOLUME 3 | OCTOBER 2003 | 777 To mediate an effective immune response, T cells must find their way to sites of infection or inflammation. Changes in T-cell homing patterns following activation are thought to result from changes in the expression of homing molecules, including adhesion molecules and chemokine receptors, however, data now show that this might not be the whole picture. Three articles in the October issue of Nature Immunology report that leukotriene B 4 (LTB 4 ) — an arachidonic-acidderived pro-inflammatory lipid — is also involved in T-cell recruitment. Andrew Luster and colleagues, who generated mice deficient for the main LTB 4 receptor BLT1, showed that LTB 4 could direct the recruitment of CD4 effector T cells. They showed that BLT1 was highly expressed by CD4 effector T-cell subsets differentiated in vitro under T helper 1 (T H 1)or T H 2-polarizing conditions and after activation in vivo. Expression of BLT1 enabled both subsets of CD4 effector T cells to move by chemotaxis towards a LTB 4 gradient, whereas naive cells were unaffected by the presence of LTB 4 . Both subsets of CD4 effector T cells also adhered to endothelial cells under flow when exposed to LTB 4 . They used their BLT1-deficient mice in an asthma model to show that the recruitment of early CD4 and CD8 T cells to the airways after aerosol challenge of previously immunized mice was dependent on the expression of BLT1. An important source of LTB 4 was shown by Vanessa Ott et al. to be activated mast cells — the sentinel cells of the tissues’ early warning system. They showed that activated mast cells could induce the migration of CD8 effector T cells through the production of LTB 4 . Therefore, LTB 4 seems to act as a link between the activation of innate immune cells and early recruitment of adaptive immune cells. Ulrich von Andrian’s group also investigated the response of CD8 T-cell subsets to LTB 4 . CD8 naive, effector and central memory T cells have distinct migratory properties in vivo; naive and central memory T cells home to secondary lymphoid tissues, whereas effector T cells migrate efficiently to inflamed tissues. The authors showed that CD8 effector T cells express high levels of BLT1, whereas CD8 memory T cells express low levels. BLT1-expressing CD8 effector T cells moved by chemotaxis towards LTB 4 , whereas naive and memory cells did not. By contrast, LTB 4 induced the rapid accumulation of both effector and memory T cells, but not naive cells, in postcapillary venules by promoting the transition from rolling to firm arrest. This effect depended on signals mediated through BLT1, as cells from the BLT1-deficient mice did not arrest in response to LTB 4 . Using a model of peritonitis, they showed that wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than BLT1-deficient effector cells, further indicating an important role for LTB 4 –BLT1 interactions in the trafficking of CD8 effector T cells in vivo. Lucy Bird References and links ORIGINAL RESEARCH PAPERS Tager, A. M. et al. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni970) | Ott, V. L. et al. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni971) | Goodarzi, K. et al. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nature Immunol. 31 August 2003 (DOI: 10.1038/ni972) identifies these molecules as specific cell-surface ligands for DNAM1. The killing of untransfected CHO-K cells by the NK-cell line NK92 depends on NKp30 (another orphan receptor). But, when these cells were transfected with the gene encoding PVR or nectin-2, NK-cell killing could only be partly inhibited by an NKp30-specific antibody, with the remainder of the cytotoxic activity being inhibited by an antibody specific for DNAM1. The functional interaction between DNAM1 and PVR and/or nectin-2 was also shown to lead to NK-cell activity for tumour target cells. These experiments showed that the killing of tumour cells by polyclonal NK cells depends on many triggering receptors, with the relative contribution of DNAM1 binding to PVR or to nectin-2 depending on the tumour type and ligand/receptor availability. Kirsty Minton

/pdf/homing-in-on-leukotrienes-4bemjlxr54.pdf

Homing in on leukotrienes

Bird flu scare

CXCR6 signalling allows natural killer cell persistence in the liver and memory-like responses.

/pdf/natural-killer-cells-making-memories-4nc1iqsyoc.pdf

Natural Killer cells: Making memories

A high-fibre diet protects against influenza virus infection by limiting lung immunopathology and enhancing antiviral T cell responses.

Lucy Bird

Papers

Homing in on leukotrienes

Bird flu scare

Natural Killer cells: Making memories

High-fibre diet beats flu

Innate immunity: The benefits of a lifelong union