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 responses: Inhibition zipped

Feeling the effects of a relentless and overloaded schedule? T cells also suffer from exhaustion and are less effective at doing their job when faced with persistent antigen, such as during chronic viral infection or cancer. Now, researchers reporting in Nature describe a mechanism that reverses the CD8+ T-cell exhaustion seen in chronic infection of mice with lymphocytic choriomeningitis virus (LCMV) and restores the ability of T cells to control the virus. LCMV is a natural pathogen of mice and, importantly for this study, strains are available that cause either acute (the Armstrong strain) or chronic (the clone 13 strain) infection. Therefore, infection with the Armstrong strain is cleared within a week and a stable pool of long-lived memory T cells is established. By contrast, the clone 13 strain establishes a persistent infection, which overwhelms the immune response and results in the generation of functionally impaired or exhausted virus-specific CD8+ T cells. To study T-cell dysfunction in chronic infection, Rafi Ahmed and colleagues first carried out gene-expression analysis of T cells that were generated following infection with each LCMV strain. Most notably, the exhausted virus-specific CD8+ T cells contained more mRNA encoding the inhibitory receptor PD1 (programmed death 1; also known as PDCD1) than functional virus-specific CD8+ T cells from Armstrong-strain-infected mice. Further analysis showed that although PD1 was transiently expressed by CD8+ T cells after infection with the Armstrong strain, it was rapidly downregulated, whereas CD8+ T cells responding to the clone 13 strain retained high PD1 expression throughout the chronic infection. Moreover, one of the ligands for PD1, PDL1, was shown to be highly expressed by persistently infected splenocytes, indicating that this inhibitory receptor–ligand interaction might regulate T-cell function during chronic LCMV infection. To test this, the authors treated persistently infected mice with a blocking antibody specific for PDL1. Remarkably, compared with untreated mice, chronically infected mice that were treated with PDL1-specific antibody underwent a marked expansion of virus-specific CD8+ T-cell populations, which had an increased ability to produce interferon-γ and tumournecrosis factor, thereby reversing the exhausted phenotype. In addition, PDL1 blockade markedly reduced the viral load and resolved infection with the clone 13 strain. The authors then showed that, even in mice that lack CD4+ T cells and therefore suffer from a more severe form of chronic infection and T-cell exhaustion, PDL1 blockade could reverse the functional impairment of the exhausted T cells and reduce the viral load. This might be of particular relevance for HIV infection, which is characterized by a loss of CD4+ T cells. Although, on the basis of these results, blockade of the PD1–PDL1 pathway for the treatment of chronic viral infection or cancer is tantalizing, prolonged disruption of this regulatory pathway can result in autoimmunity, as exemplified by PDL1-deficient mice. Lucy Bird

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T-cell responses: Reversing exhaustion

A new study in Cell provides a cellular atlas of the oral mucosa, revealing complex stromal–immune cell interactions that support inflammatory responsiveness and neutrophil recruitment.

Oral mucosa atlas.

Another way to escape the immune system's watchful eye

Stem cells could serve as a renewable source of transplantable tissue-specific cells for the treatment of immune disorders. However, the excitement surrounding this potential has been curbed by the absence of a simple in vitro system that supports the differentiation of stem cells into specific lymphoid lineages.

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Lucy Bird

Papers

Immune responses: Inhibition zipped

T-cell responses: Reversing exhaustion

Oral mucosa atlas.

Another way to escape the immune system's watchful eye

From stem cell to T cell in vitro