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

Lucky for some

NATURE REVIEWS | IMMUNOLOGY VOLUME 5 | MARCH 2005 | 187 T-cell survival in the presence of the immunosuppressive drug rapamycin depends on PIM kinases, as described in a recent report in The Journal of Experimental Medicine. PIM kinases are known to contribute to lymphoid transformation when overexpressed, but until now, their physiological role in the immune response was unclear. T-cell growth and survival following ligation of cytokine or antigen receptors is mediated, in part, through activation of the effector enzymes AKT and TOR (target of rapamycin) in the phosphatidylinositol 3-kinase pathway. However, alternative pathways of lymphocyte survival are known to exist, because AKT-deficient mice or mice treated with the TOR inhibitor rapamycin mount normal immune responses. In this paper, Craig Thompson and colleagues observed that T cells from mice deficient in PIM1 and PIM2 have increased sensitivity to rapamycin, indicating that PIM kinases might provide this alternative pathway for T-cell survival. Resting T cells do not express PIM kinases, but PIM kinase expression could be detected in T cells after culturing in the presence of the pro-survival cytokines interleukin-4 (IL-4) and IL-7 or following mitogenic stimulation with CD3and CD28-specific antibodies, with PIM1 expression being detected 3 hours after stimulation and PIM2 expression detected after 12 hours. Culturing of naive T cells with IL-4 and IL-7 also induced phosphorylation and activation of AKT and the TOR subunit p70 S6 kinase, which as expected, could be inhibited by treatment of the T cells with rapamycin. By contrast, rapamycin treatment did not prevent the induction of PIM protein expression following T-cell stimulation. In wild-type T cells or T cells deficient in PIM1 only, rapamycin treatment had little effect on cytokine-induced survival; however, treatment of PIM2-deficient T cells reduced their ability to survive in response to IL-4 or IL-7, indicating that PIM2 expression is required to compensate for TOR inhibition by rapamycin. The authors suggested that the mechanism of PIM2-dependent survival is likely to be mediated through regulation of the pro-apoptotic BCL-2-related protein BAD (BCL-2 antagonist of cell death), because phosphorylation of Ser112 of BAD, which contributes to suppression of its pro-apoptotic function, occurred 12 hours after cytokine stimulation, coincident with PIM2 expression. In addition to having a role in cytokineinduced T-cell survival, the authors show that, in the presence of rapamycin, PIM kinases are required for T-cell blastogenesis, activation and proliferation induced by stimulation with CD3and CD28-specific antibodies. Finally, the authors asked whether deficiency in PIM kinases could enhance the immunosuppressive action of rapamycin in vivo. T-cell responses were induced in wild-type or PIM-deficient mice using the superantigen toxicshock syndrome toxin (TSST). Although rapamycin treatment did not affect the activation and clonal expansion of TSST-specific T cells in wild-type mice, PIM-deficient mice had markedly suppressed TSST-induced T-cell responses following rapamycin treatment, consistent with the in vitro observations. So, although this study shows that PIM kinases can rescue T cells from the immunosuppressive effects of rapamycin both in vitro and in vivo, it does not explain why rapamycin is effective in suppressing transplant rejection in patients who have no known defects in PIM kinases. Lucy Bird References and links ORIGINAL RESEARCH PAPER Fox, C. J., Hammerman, P. S. & Thompson, C. B. The Pim kinases control rapamycin-resistant T cell survival and activation. J. Exp. Med. 201, 259–266 (2005). in the sampling of the commensal microflora and during infection with the pathogenic bacterium Salmonella typhimurium. Cx 3 cr1 mice were more susceptible to infection than heterozygous mice, probably as a result of impaired bacterial sampling and lack of transepithelial dendrites. This study describes a network of lamina-propria DCs that can directly sample luminal antigens using a mechanism distinct from that involving M cells. It remains to be determined which antigen-uptake receptors are expressed at the terminal dendrite structures and whether commensal bacteria can be distinguished from pathogens, but the authors suggest that it might be possible to target these structures to engage intestinal DCs, which could be useful for vaccine development.

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PIM kinases to the rescue

The nuclear envelope protein lamin A modulates T cell activation by linking processes at the plasma membrane, cytoplasm and nucleus.

Lucy Bird

Papers

Lucky for some

PIM kinases to the rescue

T cells: Lamin A links synapse to nucleus

IL-27 induces immunosuppressive DCs

Remodelling by TLRs