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

nism that explains how the innate immune system inhibits viral propaga­ tion but still allows the production of enough viral antigens to stimulate an effective adaptive immune response. The answer lies in a subset of macro­ phages that resists the anti viral effects of type I interferons (IFNs). Soon after systemic infection, viruses are captured by phagocytic innate immune cells, which sup­ press viral propagation through the production of type I IFNs. Indeed, in the case of mouse vesicular stomatitis virus (VSV), the authors showed that macrophages in the red pulp of the spleen and Kupffer cells in the liver effectively capture the virus and inhibit its replication in a type I IFN­ dependent manner. However, 7 hours after infection, replicating virus could be detected in CD169+ macrophages in the marginal zone of the spleen but not elsewhere. Further analysis of the marginal zone CD169+ macrophages showed that they express higher levels of ubiquitin­specific peptidase 18 (USP18) — which is known to inhibit type I IFN signalling — than F4/80+ macrophages from the red pulp. USP18 overexpression was found to be responsible for allowing VSV replication, as low amounts of viral proteins were detectable in CD169+ macrophages from Usp18–/– mice. Given that ultraviolet light­ inactivated, replication­deficient VSV generated poor antiviral B and T cell responses, the authors inves­ tigated the involvement of CD169+ macrophages in the generation of adaptive immune responses to VSV. Mice that were specifically depleted of CD169+ macrophages showed delayed and diminished B cell responses to VSV relative to control mice. Moreover, Usp18–/– mice infected with VSV had delayed antibody responses and reduced CD4+ T cell responses compared with infected wild­type mice. No such differences were observed if the mice were infected with replication­ deficient VSV, confirming that VSV replication in CD169+ macrophages was responsible for the induction of adaptive immune responses. Failure to generate strong adaptive immune responses led to the spread of the virus and death of the mice. So, by allowing viral replication in the pres­ ence of type I IFNs, marginal zone macrophages ensure the production of sufficient antigens for the activa­ tion of protective adaptive immune responses. Lucy Bird

Viral immunity: Shelter from interferons.

Researchers identify a new population of cytotoxic T cells that recognize the non-polymorphic MHC class I-related molecule MR1 on multiple different cancer cells, raising the prospect of its use as T cell-based therapy for multiple cancers.

MR1-restricted pan-cancer T cells.

/pdf/staying-alive-with-il-7-br20l8esny.pdf

Staying alive with IL-7

T cells that give rise to several distinct subsets of memory T cells: the two major ones being central memory T (TCM) cells and effector memory T (TEM) cells. A new study has shown that expression of CX3C-chemokine receptor 1 (CX3CR1) defines three distinct subsets of effector and memory CD8+ T cells and identifies a new subpopulation that is the main subset that surveys peripheral tissues. The study was motivated by an observation that CX3CR1 upregulation varies among effector T cells. Detailed analysis of this was carried out using reporter mice in which the gene encoding green fluorescent protein (GFP) was knocked into the Cx3cr1 locus (Cx3cr1+/gfp mice). Starting 5 days after acute infection with lymphocytic choriomeningitis virus, GFP expression was detected and revealed three subsets of effector T cells: CX3CR1, CX3CR1 and CX3CR1. CX3CR1 expression required cognate antigen recognition and was largely restricted to recently activated CD8+ T cells. The CX3CR1 subset had a phenotype that was typical of terminally differentiated effector T cells, being CD27–, CD127– and mostly KLRG1+, and containing few interleukin-2 (IL-2)-producing cells. In mice lacking T-bet, which is crucial for terminal differentiation, antigen-activated T cells remained mainly CX3CR1 or CX3CR1. The observation that the CX3CR1 subset contained the most polyfunctional cells, producing IL-2, interferon-γ and tumour necrosis factor, suggested that this subset represents the least differentiated cells. Together, their observations suggest a linear sequence of effector T cell differentiation from CX3CR1 to CX3CR1 to CX3CR1. Next, the authors investigated whether the differential expression of CX3CR1 affects the potential to generate memory populations, by performing adoptive transfer of each effector T cell subset into separate congenic hosts. The three subsets generated markedly different numbers of memory progeny. CX3CR1 effector T cells generated the greatest number of memory offspring, with equal numbers of CX3CR1, CX3CR1 and CX3CR1 memory T cells. CX3CR1 effector T cells generated mainly CX3CR1 and CX3CR1 memory T cells, whereas CX3CR1 effector T cells generated only CX3CR1 memory T cells. Further analysis of these memory subsets showed that the CX3CR1 cells underwent more frequent homeostatic divisions than the other memory T cells, contributing to self-renewal of the CX3CR1 pool or expanding the CX3CR1 pool. To further define the memory T cell subsets, the authors looked at their ability to home to lymph nodes. The CX3CR1 and CX3CR1 subsets responded vigorously to the CCR7 ligand CCL19 and were detectable in lymph nodes, whereas the CX3CR1 cells did not respond to CCL19 or enter lymph nodes. This suggests that the CX3CR1 subset represents classical TEM cells, and that expression of CX3CR1 delineates two previously undistinguishable subsets of TCM cells (CX3CR1 and CX3CR1 TCM cells). These TCM cell subsets were further distinguished by differential expression of CD62L, which, together with ligands for CCR7, is required for lymph node homing. CD62L upregulation was more rapid and more frequent among the CX3CR1 TCM cell subset than the CX3CR1 TCM cell subset. This was consistent with the increased ability of CX3CR1 memory T cells to access lymph nodes compared with CX3CR1 memory T cells. The current dogma poses that the TEM cell subset is the main subset responsible for surveying peripheral tissues. However, Gerlach et al. found that CX3CR1 TEM cells are largely excluded from peripheral tissues. Instead, the CD62L– fraction from the lymph-draining peripheral tissues was dominated by CX3CR1 TCM cells. Using parabiotic mice, the authors confirmed that the bloodderived CX3CR1 subset traverses the peripheral tissues and returns to the blood via the lymph, in a CD62L-independent manner. So, by subdividing CD8+ T cells on the basis of CX3CR1 expression, new subsets with differing phenotypic, homeostatic and migratory properties can be defined. Lucy Bird T C E L L S

T cells: Sorting memories.

Two new studies identify the discrete stromal cell subtypes that produce IL-33 in adipose tissue to support the immune cells that maintain adipose tissue homeostasis.

Lucy Bird

Papers

Viral immunity: Shelter from interferons.

MR1-restricted pan-cancer T cells.

Staying alive with IL-7

T cells: Sorting memories.

Stromal IL-33 balances fat stores.