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Tissue-resident macrophages can derive from yolk sac macrophages (YS-Macs), fetal liver monocytes (FL-MOs), or adult bone-marrow monocytes (BM-MOs). The relative capacity of these precursors to colonize a niche, self-maintain, and perform tissue-specific functions is unknown. We simultaneously transferred traceable YS-Macs, FL-MOs, and BM-MOs into the empty alveolar macrophage (AM) niche of neonatal...
Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and...
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an “alternative...
Recognition of DNA and RNA by endosomal and cytosolic sensors constitutes a central element in the detection of microbial invaders by the innate immune system. However, the capacity of these sensors to discriminate between microbial and endogenous nucleic acids is limited. Over the past few years, evidence has accumulated to suggest that endogenous DNA or RNA species can engage nucleic-acid-sensing...
Generally, two signals are required to activate the NLRP3 inflammasome. In this issue of Immunity, Hornung and colleagues (2016) describe an alternative inflammasome activation pathway in human monocytes triggering activation of the NLRP3 inflammasome in response to a single stimulus.
Non-alcoholic fatty liver disease is associated with hepatocellular carcinoma. In the March 10 issue of Nature, Greten and colleagues report that this metabolic disruption affects tumor surveillance by depleting CD4+ T helper cells through lipotoxic mechanisms associated with NAFLD.
VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire...
The participation of a specific subset of B cells and how they are regulated in cancer is unclear. Here, we demonstrate that the proportion of CD5+ relative to interleukin-6 receptor α (IL-6Rα)-expressing B cells was greatly increased in tumors. CD5+ B cells responded to IL-6 in the absence of IL-6Rα. IL-6 directly bound to CD5, leading to activation of the transcription factor STAT3 via gp130 and...
In this issue of Immunity, Prinz and colleagues (2016) describe an unexpected mechanism underlying the role of type I interferon in the initiation of cognitive impairment and sickness behavior during viral infection through induction of chemokine CXCL10 in central nervous system epithelial and endothelial cells.
Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103+ dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and...
Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated. Consistent with this, BAI1-deficient mice...
The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ+ and CD4+CD8αα+ T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent...
MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27,...
Although antigen recognition mediated by the T cell receptor (TCR) influences many facets of Foxp3+ regulatory T (Treg) cell biology, including development and function, the cell types that present antigen to Treg cells in vivo remain largely undefined. By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we demonstrated an essential role for dendritic cells (DCs)...
Allergic disease affects millions. Despite many advances in our understanding of the immune system in the past century, the physiologic underpinning for the existence of allergy remains largely mysterious. Food allergies, in particular, have increased dramatically in recent years, adding a new sense of urgency to unraveling this mystery. The concurrence of significant lifestyle changes in Western...
Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer’s patch (PP) Tfh cells were essential for...
Activation of T cells is mediated by the engagement of T cell receptors (TCRs) followed by calcium entry via store-operated calcium channels. Here we have shown an additional route for calcium entry into T cells—through the low-voltage-activated T-type CaV3.1 calcium channel. CaV3.1 mediated a substantial current at resting membrane potentials, and its deficiency had no effect on TCR-initiated calcium...
Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein...
In this issue of Immunity, Kweon and colleagues (2016) report a novel antiviral cocktail approach to specifically reduce the virome component of the intestinal microbiota. Using this strategy, they generate compelling evidence that the virome provides protection from gut inflammatory conditions.
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