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Mechanisms forHelicobacter pylori(Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitantHpinfection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA-seq showed thatHp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucinMuc4and the growth factor amphiregulin. Metaplastic pit cells were associated with macrophage and T cell inflammation and prevented by gastric immunosuppression. Lineage tracing showed thatMuc4was not dependent on cell-intrinsic KRAS activity, and lineage-derived cells had a limited propensity for growth as organoids, demonstrating that metaplastic pit cells are largely not self- renewing. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify anHp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven byHp-dependent inflammation.Statement of SignificanceUsing a mouse model, we have delineated metaplastic pit cells as a pre-cancerous cell type whose expansion requiresH. pylori-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal CD4(+) T lymphocytes differentiate into functional subtypes with regulatory or effector functions. The development of small intestine intraepithelial lymphocytes that co-express CD4 and CD8αα homodimers (CD4IELs) depends on the microbiota. However, the identity of the microbial antigens recognized by CD4(+) T cells that can differentiate into CD4IELs remains unknown. We identified β-hexosaminidase, a conserved enzyme across commensals of the Bacteroidetes phylum, as a driver of CD4IEL differentiation. In a mouse model of colitis, β-hexosaminidase–specific lymphocytes protected against intestinal inflammation. Thus, T cells of a single specificity can recognize a variety of abundant commensals and elicit a regulatory immune response at the intestinal mucosa.

Childhood undernutrition is associated with dysbiosis and dampened vaccine responses. Understanding how nutrients influence the microbiota and immunity is critical for vaccine efficacy. In this issue of Cell Host & Microbe, Di Luccia et al. and Huus et al. reveal that nutrition affects IgA responses to the microbiota and oral vaccines.

Summary Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC., Graphical abstract, Highlights Intestinal prematurity is characterized by the lack of efficient IL-22 production rIL-22 enhances the regeneration and integrity of intestinal epithelium during NEC rIL-22-driven antimicrobial response does not affect neonatal microbiome composition, Necrotizing enterocolitis (NEC) is a deadly intestinal disease with limited treatment options. Interleukin (IL)-22 plays a role in controlling intestinal inflammation in adult animal models of gastrointestinal disease. Mihi et al. demonstrate that IL-22 can attenuate intestinal inflammation by promoting epithelial regeneration in a neonatal mouse model of NEC.

Though critical for preventing fatal sepsis, the mechanisms mediating the capture of bloodstream bacteria are incompletely understood. New work by Zeng et al. (2018) demonstrates that estrogen-regulated innate antibodies protect females and newborns from death following bloodstream infection with enteropathogenic Eschericia coli.

B-1a cells play an important role in mediating tissue homeostasis and protecting against infections. They are the main producers of ‘natural’ IgM, spontaneously secreted serum antibodies predominately reactive to self antigens, like phosphatidylcholine (PtC), or antigens expressed by the intestinal microbiota. The mechanisms that regulate the B-1a immunoglobulin (Ig) repertoire and their antibody secretion remain poorly understood. Here, we use a novel reporter mouse to demonstrate that production of self- and microbiota-reactive antibodies is linked to BCR signaling in B-1a cells. Moreover, we show that Toll-like receptors (TLRs) are critical for shaping the Ig repertoire of B-1a cells as well as regulating their antibody production. Strikingly, we find that both the colonization of a microbiota as well as microbial-sensing TLRs are required for anti-microbiota B-1a responses, whereas nucleic-acid sensing TLRs are required for anti-PtC responses, demonstrating that linked activation of BCR and TLRs controls steady state B-1a responses to both self and microbiota-derived antigens.

Context shapes anticommensal immunity The gut bacterium Akkermansia muciniphila is associated with protection from obesity, enhanced wound healing, and augmented antitumor responses. Ansaldo et al. found that this microbe induces antigen-specific immunoglobulin G1 (IgG1) antibodies generated by B cells with CD4 + T cell help. This is in contrast to most anticommensal responses, which involve the T cell–independent production of IgA antibodies. In a gnotobiotic setting in which all components of the microbiome are defined, A. muciniphila –specific T cells expanded only when A. muciniphila was present. The T cells primarily displayed a phenotype associated with B cell help. However, in mice with a conventional gut microbiota, other proinflammatory A. muciniphila –specific T cell populations also expanded. Thus, anti– A. muciniphila immunity is context dependent, which may explain the variable immune responses to this microbe reported in patients. Science , this issue p. 1179

Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life.

To maintain a symbiotic relationship between the host and its resident intestinal microbiota, appropriate mucosal Tcell responses to commensal antigens must be established. Mice acquire both IgG and IgA maternally; the former has primarily been implicated in passive immunity to pathogens while the latter mediates host-commensal mutualism. Here, we report the surprising observation that mice generate Tcell-independent and largely Toll-like receptor (TLR)-dependent IgG2b and IgG3 antibody responses against their gut microbiota. We demonstrate that maternal acquisition of these antibodies dampens mucosal T follicular helper responses and subsequent germinal center B cell responses following birth. This work reveals a feedback loop whereby Tcell-independent, TLR-dependent antibodies limit mucosal adaptive immune responses to newly acquired commensal antigens and uncovers a broader function for maternal IgG.

Summary Foxp3 + regulatory T (Treg) cells limit inflammatory responses and maintain immune homeostasis. Although comprised of several phenotypically and functionally distinct subsets, the differentiation of specialized Treg cell populations within the periphery is poorly characterized. We demonstrate that the development of T-bet + Treg cells that potently inhibit T helper 1 (Th1) cell responses was dependent on the transcription factor STAT1 and occurred directly in response to interferon-γ produced by effector T cells. Additionally, delayed induction of the IL-12Rβ2 receptor component after STAT1 activation helped ensure that Treg cells do not readily complete STAT4-dependent Th1 cell development and lose their ability to suppress effector T cell proliferation. Thus, we define a pathway of abortive Th1 cell development that results in the specialization of peripheral Treg cells and demonstrate that impaired expression of a single cytokine receptor helps maintain Treg cell-suppressive function in the context of inflammatory Th1 cell responses.

Abdominal apoplexy, or idiopathic spontaneous intraperitoneal hemorrhage, is a rare and often fatal condition resulting from a variety of disease processes affecting the arterial and venous abdominal vasculature. Preoperative and intraoperative diagnosis and treatment of abdominal apoplexy are challenging. The source of bleeding may remain elusive even after careful autopsy dissection given the absence of intravascular pressure. Despite these challenges, early diagnosis and rapid treatment remain central to a successful outcome, as nonsurgical mortality has approached 100%. Presented here are two fatal cases of abdominal apoplexy, one involving a patient with arterial dissection of the gastroduodenal artery and one involving rupture of the superior mesenteric-portal venous system with perivascular pseudoaneurysm formation.

Inhibition of T reg cells by type I IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection., Regulatory T (T reg) cells play an essential role in preventing autoimmunity but can also impair clearance of foreign pathogens. Paradoxically, signals known to promote T reg cell function are abundant during infection and could inappropriately enhance T reg cell activity. How T reg cell function is restrained during infection to allow the generation of effective antiviral responses remains largely unclear. We demonstrate that the potent antiviral type I interferons (IFNs) directly inhibit co-stimulation–dependent T reg cell activation and proliferation, both in vitro and in vivo during acute infection with lymphocytic choriomeningitis virus (LCMV). Loss of the type I IFN receptor specifically in T reg cells results in functional impairment of virus-specific CD8+ and CD4+ T cells and inefficient viral clearance. Together, these data demonstrate that inhibition of T reg cells by IFNs is necessary for the generation of optimal antiviral T cell responses during acute LCMV infection.

The isolated finding of calcific deposits within axillary lymph nodes on mammography suggests a broad range of differential diagnoses, from benign causes such as granulomatous reaction secondary to previous histoplasmosis infection to malignancies such as breast cancer and metastatic disease from extramammary primary malignancies. Therefore, the isolated finding of intranodal calcium may warrant biopsy for a definitive diagnosis when a benign etiology is not apparent. We present a patient with isolated axillary lymph node densities on mammography and chest computed tomography, which were subsequently proven to represent deposition of tattoo pigment.

Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells prevent autoimmune disease, maintain immune homeostasis and modulate immune responses during infection. To accomplish these tasks, T(Reg) cell activity is precisely controlled, and this requires T(Reg) cells to alter their migratory, functional and homeostatic properties in response to specific cues in the immune environment. We review progress in understanding the diversity of T(Reg) cells, T(Reg) cell function in different anatomical and inflammatory settings, and the influence of the immune environment on T(Reg) cell activity. We also consider how these factors affect immune-mediated disease in the contexts of infection, autoimmunity, cancer and transplantation.

Several subsets of Foxp3+ regulatory T cells are known to exist. Campbell and colleagues show that one subset of regulatory T cells requires the transcription factor T-bet during T helper type 1–mediated immune responses in vivo. Several subsets of Foxp3+ regulatory T cells (Treg cells) work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper type 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1 cell–mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type 1 inflammation. Thus, in a subset of CD4+ T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in Treg cells with unique homeostatic and migratory properties optimized for the suppression of TH1 responses in vivo.

How B cell tolerance is retained during somatic hypermutation in germinal centers is incompletely understood. Two studies now show that Foxp3+ regulatory T cells undergo functional specialization to limit the magnitude of the germinal center response, and they may contribute to our understanding of how germinal center–mediated autoimmunity is prevented (pages 975–982 and 983–988).

Regulatory T cells (TR) expressing the transcription factor Foxp3 play a critical role in preventing autoimmunity and restraining immune responses during infection. To accomplish these tasks, several subsets of TR work in concert to maintain normal immune homeostasis in secondary lymphoid tissues and at peripheral sites. However, the molecular basis underlying the phenotypic and functional differences of TR subsets remain obscure. Here, we show that during type 1 inflammatory responses, Foxp3+ TR upregulate the TH1-specifying transcription factor T-bet. These Foxp3+T-bet+ cells retain regulatory function, and do not produce the pro-inflammatory TH1 cytokine IFN-γ. Within TR, T-bet directs expression of the TH1-associated chemokine receptor CXCR3, and T-bet+ TR accumulate at sites of microbial replication in mice during persistent infection with Mycobacterium tuberculosis. T-bet-deficient TR show diminished proliferation and are outcompeted by wild type TR during strong TH1 responses in vivo. Furthermore, T-bet expression by TR is required for their proper homeostasis and function during TH1-driven autoimmunity. Thus, our data define a unique population of CD4+ T cells in which the activities of Foxp3 and T-bet are overlaid, resulting in functional TR capable of expanding during type-1 inflammation and suppressing TH1 responses in vivo. (NIH -DK072295, AI067750, AI069889)

IgA antibodies help maintain intestinal immune homeostasis with resident commensal species; however, the precise mechanisms regulating IgA induction and the epitopes recognized by these antibodies remain incompletely understood. In this issue of Cell Host & Microbe, Cullender et al. (2013) demonstrate that TLR5-dependent induction of anti-flagellin antibodies prevents commensal association with the intestinal mucosa by limiting bacterial motility.