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The mammalian gastrointestinal tract is home to a dense community of resident bacteria and is also exposed to microorganisms from the external environment. The epithelial surface of the intestine plays a critical role in host protection by producing a diverse repertoire of antimicrobial proteins that directly kill or hinder the growth of microorganisms. Here we discuss the general principles that...
Clustered regularly interspaced palindromic repeats (CRISPR)-associated (Cas9) technology has proven a formidable addition to our armory of approaches for genomic editing. Derived from pathways in archaea and bacteria that mediate the resistance to exogenous genomic material, the CRISPR-Cas9 system utilizes a short single guide RNA (sgRNA) to direct the endonuclease Cas9 to virtually anywhere in the...
The cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1 + myeloid cells were uniformly distributed in the BM, and all c-kit + progenitor cells were...
Reprogramming of cellular metabolism is crucial for T cells responding to environmental cues. Blagih et al. (2015) reveal that the kinase AMPK directs metabolic adaption of effector T cells upon nutrient limitation and contributes to immune responses in vivo.
Transforming growth factor-beta (TGF-β) suppresses T cell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates T cell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal...
The biogenesis of beige fat is poorly understood. In recent issues of Nature and Cell, Brestoff et al. (2014) and Lee et al. (2015) demonstrate that resident innate lymphoid cells in subcutaneous fat generate and activate beige adipocytes, producing thermogenesis.
The number of T cells specific for various antigens can vary dramatically. In this issue of Immunity, Nelson et al. (2015) report that these differences might be, at least in part, set by the number of cross-reactive self peptides encountered by T cells during development.
Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated...
Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry...
Notch receptors are widely expressed and have recognized functions in thymocytes and mature T cells. In this issue, Laky et al. (2015) show that Notch interactions with Delta-like ligand 4 (DLL4) amplify priming of naive T cells.
The nature and functions of cells creating hematopoietic niches during inflammation remain incompletely understood. In this issue of Immunity, Kwak et al. (2015) reveal that myeloid cell-produced reactive oxygen species stimulate proliferation of myeloid progenitors establishing an additional mechanism to regulate hematopoiesis.
T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naive CD4 + T cell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant because systemic expression...
Kupffer cells, the phagocytes of fetal origin that line the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, we found that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, which was followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer cell death also triggered a type 2 response...
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive...
The probabilistic expression of cytokine genes in differentiated T helper (Th) cell populations remains ill defined. By single-cell analyses and mathematical modeling, we show that one stimulation featured stable cytokine nonproducers as well as stable producers with wide cell-to-cell variability in the magnitude of expression. Focusing on interferon-γ (IFN-γ) expression by Th1 cells, mathematical...
Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NF-κB inhibitor A20 is a ubiquitin-modifying enzyme that might be critical in preventing human inflammatory diseases. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to...
Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling,...
Liver Kupffer cells (KCs) are self-maintained tissue-resident macrophages. In this issue of Immunity, Blériot et al. demonstrate that bacterial infection leads to KC necroptosis and quantitative replacement by monocyte-derived macrophages that contribute to antibacterial immunity and restoration of tissue integrity.
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