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Certain bacterial colonists induce a highly specific T cell response. A hallmark of this encounter is that adaptive immunity develops preemptively, in the absence of an infection. However, the functional properties of colonist-induced T cells are not well defined, limiting our ability to understand anticommensal immunity and harness it therapeutically. We addressed both challenges by engineering the skin bacterium Staphylococcus epidermidis to express tumor antigens anchored to secreted or cell-surface proteins. Upon colonization, engineered S. epidermidis elicits tumor-specific T cells that circulate, infiltrate local and metastatic lesions, and exert cytotoxic activity. Thus, the immune response to a skin colonist can promote cellular immunity at a distal site and can be redirected against a target of therapeutic interest by expressing a target-derived antigen in a commensal.

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

ObjectivesPremature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE.MethodsEighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed.ResultsSeventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose.ConclusionPGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE.Trial registration numberNCT02338999.

International audience; The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake

TCRαβ+ CD8α+ CD8β− intraepithelial lymphocytes (CD8αα IEL) differentiate from thymic IEL precursors (IELp) and contribute to gut homeostasis. However, their development remains poorly understood. Here we show that the zinc finger transcription factor LRF, encoded by Zbtb7a, is highly expressed in both CD8αα+ IELs and in IELp and serves in a cell-intrinsic manner to promote IEL differentiation. Mice genetically deficient for LRF (Cd4-Cre Zbtb7afl/fl) lack CD8αα+ IELs, contrasting with largely conserved numbers of conventional CD8αβ+ T cells in the thymus and the secondary lymphoid organs. Unlike their wild-type counterparts, LRF-deficient IELp failed to prevent colitis caused by adoptive transfer of CD4+ T cells in T cell-deficient mice. LRF disruption affects neither the development of thymic IELp, nor their in vitro expansion or differentiation in response to IL-15. However, Cd4-Cre Zbtb7afl/fl mice accumulate CD8αα+ T cells in the spleen, unlike wild-type controls, suggesting impaired migration of IELp to the gut. Single-cell RNA sequencing found LRF necessary for the expression of genes characteristic of the most mature IELp, including Itgb7, encoding the β7 subunit of α4β7. Chromatin immunoprecipitation and gene regulatory network analyses both defined Itgb7 as an LRF target. Our study identifies LRF as an essential transcriptional regulator of IELp maturation in the thymus and subsequent migration to the intestinal epithelium.

Plasmacytoid dendritic cells (pDCs) have been shown to play an important role during immune responses, ranging from initial viral control through the production of type I interferons to antigen presentation. However, recent studies uncovered unexpected heterogeneity among pDCs. We identified a previously uncharacterized immune subset, referred to as pDC-like cells, that not only resembles pDCs but also shares conventional DC (cDC) features. We show that this subset is a circulating precursor distinct from common DC progenitors, with prominent cDC2 potential. Our findings from human CD2-iCre and CD300c-iCre lineage tracing mouse models suggest that a substantial fraction of cDC2s originates from pDC-like cells, which can therefore be referred to as pre-DC2. This precursor subset responds to homeostatic cytokines, such as macrophage colony stimulating factor, by expanding and differentiating into cDC2 that efficiently prime T helper 17 (T H 17) cells. Development of pre-DC2 into CX3CR1 + ESAM − cDC2b but not CX3CR1 − ESAM + cDC2a requires the transcription factor KLF4. Last, we show that, under homeostatic conditions, this developmental pathway regulates the immune threshold at barrier sites by controlling the pool of T H 17 cells within skin-draining lymph nodes.

The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

Unbiased plasma proteomics in a matched case-control study of treated people with human immunodeficiency virus (PWH) revealed the complement cascade as being among the top pathways enriched in PWH. Specific complement components, namely C5, associated significantly with non-AIDS comorbidity prevalence, and did so more strongly than previously established predictive biomarkers.

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminthHeligmosomoides polygyrus bakerialters antigen-specific antibody and cellular immune responses to oral and parenteral vaccination in mice. We found that oral vaccination of mice with a clinically relevant, live, attenuated, recombinantSalmonellavaccine that expresses chicken egg ovalbumin (Salmonella-OVA) disrupts ovalbumin-specific regulatory T cell networks in the gut associated lymphoid tissue and promotes T-effector responses to OVA. Chronic intestinal helminth infection significantly reduced Th1-skewed antibody responses to oral vaccination withSalmonella-OVA. Activated, adoptively-transferred, OVA-specific CD4+T cells accumulated in draining mesenteric lymph nodes (MLN) of vaccinated mice, irrespective of their helminth-infection status. However, helminth infection increased the frequencies of adoptively-transferred OVA-specific CD4+T cells producing IL-4 and IL-10 in the MLN. Chronic intestinal helminth infection also significantly reduced Th2-skewed antibody responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest helminth-induced impairment of vaccine antibody responses may be driven by the development of IL-10-secreting CD4+T regulatory cells. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.

Unique gut microbiota compositions have been associated with inflammatory diseases, but identifying gut bacterial functions linked to immune activation in humans remains challenging. Translocation of pathogens from mucosal surfaces into peripheral tissues can elicit immune activation, although whether and which gut commensal bacteria translocate in inflammatory diseases is difficult to assess. We report that a subset of commensal gut microbiota constituents that translocate across the gut barrier in mice and humans are associated with heightened systemic immunoglobulin G (IgG) responses. We present a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the cladesCollinsella,Bifidobacterium,Lachnospiraceae, andRuminococcaceae. These and other taxa identified as translocating bacteria or targets of systemic immunity in IBD concomitantly exhibited heightened transcriptional activity and growth rates in IBD patient gut microbiomes. Our approach represents a complementary tool to illuminate interactions between the host and its gut microbiota and may provide an additional method to identify microbes linked to inflammatory disease.

Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria–driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.

Background and aims Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. Approach and results Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. Conclusions APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.

New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573

Low concordance between studies that examine the role of microbiota in human diseases is a pervasive challenge that limits the capacity to identify causal relationships between host-associated microorganisms and pathology. The risk of obtaining false positives is exacerbated by wide interindividual heterogeneity in microbiota composition1, probably due to population-wide differences in human lifestyle and physiological variables2 that exert differential effects on the microbiota. Here we infer the greatest, generalized sources of heterogeneity in human gut microbiota profiles and also identify human lifestyle and physiological characteristics that, if not evenly matched between cases and controls, confound microbiota analyses to produce spurious microbial associations with human diseases. We identify alcohol consumption frequency and bowel movement quality as unexpectedly strong sources of gut microbiota variance that differ in distribution between healthy participants and participants with a disease and that can confound study designs. We demonstrate that for numerous prevalent, high-burden human diseases, matching cases and controls for confounding variables reduces observed differences in the microbiota and the incidence of spurious associations. On this basis, we present a list of host variables that we recommend should be captured in human microbiota studies for the purpose of matching comparison groups, which we anticipate will increase robustness and reproducibility in resolving the members of the gut microbiota that are truly associated with human disease.

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.

Loss of gut mucosal integrity and an aberrant gut microbiota are proposed mechanisms contributing to chronic inflammation and increased morbidity and mortality during antiretroviral-treated HIV disease. Sexual practice has recently been uncovered as a major source of microbiota variation, potentially confounding prior observations of gut microbiota alterations among persons with HIV (PWH). To overcome this and other confounding factors, we examine a well-powered subset of AGEhIV Cohort participants comprising antiretroviral-treated PWH and seronegative controls matched for age, body-mass index, sex, and sexual practice. We report significant gut microbiota differences in PWH regardless of sex and sexual practice including Gammaproteobacteria enrichment, Lachnospiraceae and Ruminococcaceae depletion, and decreased alpha diversity. Men who have sex with men (MSM) exhibit a distinct microbiota signature characterized by Prevotella enrichment and increased alpha diversity, which is linked with receptive anal intercourse in both males and females. Finally, the HIV-associated microbiota signature correlates with inflammatory markers including suPAR, nadir CD4 count, and prevalence of age-associated noncommunicable comorbidities., The role of sexual practice in HIV-associated gut microbiota remains poorly understood. Here, in a cohort of chronically treated HIV-infected people, the authors show microbiome signatures to be independent of sex and sexual practice and that the extent of dysbiosis correlates with nadir CD4, inflammatory markers, and comorbidities.

Atypical T cells take a different path Conventional T cells recognize peptides that are presented by polymorphic major histocompatibility complexes (MHCs). By contrast, many tissue-resident T cells, such as mucosal-associated invariant T cells, invariant natural killer T cells, and γδ T cells, respond to modified peptides and small molecules presented by conserved MHC-like molecules. Unconventional T cells are important for host defense and tissue repair and seed tissues during critical early-life windows of development. Constantinides and Belkaid review recent advances describing how unconventional T cell subsets compete for early-life signals, including those from the microbiota, which instruct their development and have enduring consequences for the health of the host. —STS

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces, and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis (Mtb) infection alters the phenotype and function of lung IL-18Rα

Puel and Casanova and Kisand et al . challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire -deficient mice, with strong corroborative evidence in patients.

Mom’s IL-6 rewires baby’s gut immunity Most infections that occur during pregnancy are mild and transient. However, whether such pathogen encounters can shape the long-term trajectory of the offspring’s immune system remains unclear. Lim et al . infected pregnant mice with the common food-borne pathogen Yersinia pseudotuberculosis (YopM) (see the Perspective by Amir and Zeng). Although the infection was maternally restricted and short-lived, the offspring harbored greater numbers of intestinal T helper 17 cells into adulthood. Interleukin-6 (IL-6) mediated this tissue-restricted effect by acting on fetal intestinal epithelium during development. Although offspring from mothers infected with YopM or injected with IL-6 showed enhanced resistance to oral infection with Salmonella Typhimurium, they also exhibited higher susceptibility toward enteric inflammatory disease. —STS

Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy. Vancomycin alone similarly enhanced the susceptibility to invasive fungal infection and systemic bacterial co-infection. Mechanistically, vancomycin reduced the frequency of gut Th17 cells associated with impaired proliferation and RORγt expression. Vancomycin's effects on Th17 cells were indirect, manifesting only in vivo in the presence of dysbiosis. In humans, antibiotics were associated with an increased risk of invasive candidiasis and death after invasive candidiasis. Our work highlights the importance of antibiotic stewardship in protecting vulnerable patients from life-threatening infections and provides mechanistic insights into a controllable iatrogenic risk factor for invasive candidiasis.

While the microbiota has been associated with diseases states, how specific alterations in composition, function, or localization contribute to pathologies remains unclear. The ability of defined microbes to translocate has been linked to diseases including inflammatory bowel disease (IBD) and was shown to promote responses to immune checkpoint therapy. However, scalable and unbiased tools to uncover microbes with enhanced ability to translocate are limited. Herein, we developed an approach to utilize systemic IgG in an unbiased, culture-independent, and high-throughput fashion as a biomarker to identify gut microbiota members that are capable of translocation across the gastrointestinal barrier. We validate these findings in a cohort of human subjects, and highlight a number of microbial taxa against which elevated IgG responses are unique to subjects with IBD includingCollinsella, Bifidobacterium, Faecalibacterium,andBlautia spp.CollinsellaandBifidobacteriumtaxa identified as translocators and targets of immunity in IBD also exhibited heightened bacterial activity and growth rates in Crohn’s disease subjects. Our approach may represent a complementary tool to illuminate privileged interactions between host and its microbiota, and may provide an additional lens by which to uncover microbes linked to disease processes.One Sentence SummaryCirculating microbiota-specific IgG can identify gut microbiota constituents capable of crossing the gut barrier.

We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in two kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including tumor-necrosis factor and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2

The immune system has coevolved with extensive microbial communities living on barrier sites that are collectively known as the microbiota. It is increasingly clear that microbial antigens and metabolites engage in a constant dialogue with the immune system, leading to microbiota-specific immune responses that occur in the absence of inflammation. This form of homeostatic immunity encompasses many arms of immunity, including B cell responses, innate-like T cells, and conventional T helper and T regulatory responses. In this review we summarize known examples of innate-like T cell and adaptive immunity to the microbiota, focusing on fundamental aspects of commensal immune recognition across different barrier sites. Furthermore, we explore how this cross talk is established during development, emphasizing critical temporal windows that establish long-term immune function. Finally, we highlight how dysregulation of immunity to the microbiota can lead to inflammation and disease, and we pinpoint outstanding questions and controversies regarding immune system–microbiota interactions.

BackgroundThe human intestinal microbiome is a complex community that contributes to host health and disease. In addition to normal microbiota, pathogens like carbapenem-resistant Enterobacteriaceae may be asymptomatically present. When these bacteria are present at very low levels, they are often undetectable in hospital surveillance cultures, known as occult or subclinical colonization. Through the use of antibiotics, these subclinical pathogens can increase to sufficiently high levels to become detectable, in a process called outgrowth. However, little is known about the interaction between gut microbiota and Enterobacteriaceae during occult colonization and outgrowth.ResultsWe developed a clinically relevant mouse model for studying occult colonization. Conventional wild-type mice without antibiotic pre-treatment were exposed to K. pneumoniae but rapidly tested negative for colonization. This occult colonization was found to perturb the microbiome as detected by both 16S rRNA amplicon and shotgun metagenomic sequencing. Outgrowth of occult K. pneumoniae was induced either by a four-antibiotic cocktail or by individual receipt of ampicillin, vancomycin or azithromycin, which all reduced overall microbial diversity. Notably, vancomycin was shown to trigger K. pneumoniae outgrowth in only a subset of exposed animals (outgrowth-susceptible). To identify factors that underlie outgrowth susceptibility, we analyzed microbiome-encoded gene functions and were able to classify outgrowth-susceptible microbiomes using pathways associated with mRNA stability. Lastly, an evolutionary approach illuminated the importance of xylose metabolism in K. pneumoniae colonization, supporting xylose abundance as a second susceptibility indicator. We showed that our model is generalizable to other pathogens, including carbapenem-resistant Escherichia coli and Enterobacter cloacae.ConclusionsThis study suggests that microbiota mRNA and small-molecule metabolites may be used to predict outgrowth-susceptibility. Our modeling of occult colonization and outgrowth could help the development of strategies to mitigate the risk of subsequent infection and transmission in medical facilities and the wider community.

The mammalian immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal IL-6 produced in response to infection can specifically and directly impose epigenetic changes on fetal intestinal epithelial cells. Such imprinting is associated with long-lasting impacts on intestinal immune homeostasis, characterized by enhanced tonic immunity to the microbiota and heightened Th17 responses within the gut, but not at other barrier sites. Furthermore, the offspring from IL-6-exposed dams developed enhanced protective immunity to gastrointestinal infection. Together, this work demonstrates that maternal infection experienced during pregnancy can be coopted by the fetus to promote long-term tissue-specific fitness.Summary sentenceInfection-induced maternal IL-6 impacts offspring epithelial cells, resulting in heightened immunity to the microbiota and pathogens.

INTRODUCTION: Studies of monogenic diseases have uncovered the importance of immune pathways in human tissue-specific immunity and antimicrobial defense. In particular, human inborn errors of the interleukin-17 (IL-17) receptor signaling pathway and corroborating mouse studies have established the critical contribution of type 17 responses inmucosa-specific fungal surveillance. The yeast Candida albicans is the signature pathogen in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an inherited autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. Fungal disease in APECED is limited to chronic mucocutaneous candidiasis (CMC) without dissemination, suggesting a central defect in barrier immunity. RATIONALE: AIRE deficiency impairs central immune tolerance, resulting in the generation of pathogenic autoreactive T cells and autoantibodies directed against many tissue-specific antigens and certain cytokines, including “type 17” cytokines. However, although a majority of APECED patients with CMC have type 17 cytokine–targeted autoantibodies, whether type 17 or other localmucosal immune responses are affected in AIRE deficiency has not been determined. Here, we broadly investigated oral mucosal immune responses both in a model of oropharyngeal candidiasis in Aire(−/−) mice and in a large cohort of APECED patients. RESULTS: Type 17 immune responses at the oralmucosa were unexpectedly intact in mice and humans with AIRE deficiency. To define alternative mechanisms of fungal susceptibility, we investigated Aire(−/−) mice, which exhibited oralmucosa-specific susceptibility to candidiasis without dissemination and controlled experimental challenges with viruses and bacteria normally, thereby phenocopying the infection predisposition observed in APECED patients. Notably, Aire(−/−) CD4(+) and CD8(+) T cells accumulated in increased numbers and displayed an activated and proliferative phenotype within the oral mucosa and were both necessary and sufficient to drive mucosal fungal infection in Aire deficiency. Enhanced production of interferon-γ (IFN-γ) by Aire(−/−) mucosal CD4(+) and CD8(+) T cells resulted in exacerbated IFN-γ/STAT1-mediated responses in the oral mucosa, which promoted IFN-γ–dependent epithelial barrier disruption and mucosal fungal susceptibility. Genetic and pharmacologic inhibition of IFN-γ or JAK-STAT signaling ameliorated mucosal fungal disease in Aire(−/−) mice. Aberrant type 1 responseswere also observed in the oral mucosa of APECED patients. CONCLUSION: We identify a T cell–dependent interferonopathy as a critical local mucosal mechanism underlying CMC in APECED. Although type 17 mucosal immunity is critical for host defense against barrier infection, mucosal type 17 responses were intact in patients with APECED and in a mouse model of the disease. These findings show that, in contrast to the known protective roles of T cells in antifungal host defense, aberrant type 1–associated T cell responses can be detrimental to antifungal mucosal immunity. They also support a paradigm by which exaggerated immunopathology may facilitate susceptibility to mucosal fungal infection by impairing the integrity of the epithelial barrier. Finally, they pave the way for investigating type 1 mucosal responses in other CMC-manifesting diseases and for the prevention and treatment of CMC in APECED patients using FDA-approved therapies that target IFN-γ or JAK-STAT signaling.

Background Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Methods Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1–5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Results Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Conclusions Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of nociceptive nerves in homeostatic adaptive immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuro-immune interaction between commensal-specific T lymphocytes and skin-innervating nociceptive neurons through secretion of calcitonin gene-related peptide (CGRP). We observed upregulation of the CGRP co-receptor, receptor activity modifying protein 1 (RAMP1), in T lymphocytes induced by topical colonization of the human skin commensal Staphylococcus epidermidis, but not in T cell populations elicited by cutaneous infection or inflammation. Utilizing intravital imaging, we observed that commensal-specific T cells interact intimately and dynamically with skin nociceptive nerves in a CGRP-dependent manner. Importantly, CGRP secreted from nociceptors acts directly on commensal-specific T cells via RAMP1 to regulate their accumulation in the tissues, cytokine production and motility in vivo. Activation or inhibition of nociceptive neurons functionally tune commensal-specific T cells and optimize their responses to ensuing heterologous infections or damaging challenges in the skin. The ability of the somatosensory neurons to participate in the highly specific and potentially long-lasting adaptive immune response to the microbiota underscores the functional versatility and plasticity of commensal-specific T lymphocytes that can be swiftly tuned to diverse arrays of sensory modalities ranging from thermosensation to noxious pain under steady state and pathology. Supported by Damon Runyon Cancer Research Foundation

Ligands derived from the gut microbiota enhance cancer immunotherapy

Academic Editors at JEM share their experiences of being women in STEM and suggest future directions to support the career of female scientists., Before one can think of the challenges that face women in science and the hurdles that impair their development into leadership positions, it is worth considering the diversity within the collective of women scientists at the level of culture and past experience and life events.

Background The improvements in genomics methods coupled with readily accessible high-throughput sequencing have contributed to our understanding of microbial species, metagenomes, infectious diseases and more. To maximize the impact of these genomics studies, it is important that data from biological samples will become publicly available with standardized metadata. The availability of data at public archives provides the hope that greater insights could be obtained through integration with multi-omics data, reproducibility of published studies, or meta-analyses of large diverse datasets. These datasets should include a description of the host, organism, environmental source of the specimen, spatial-temporal information and other relevant metadata, but unfortunately these attributes are often missing and when present, they show inconsistencies in the use of metadata standards and ontologies. Results METAGENOTE (https://metagenote.niaid.nih.gov) is a web portal that greatly facilitates the annotation of samples from genomic studies and streamlines the submission process of sequencing files and metadata to the Sequence Read Archive (SRA) (Leinonen R, et al, Nucleic Acids Res, 39:D19-21, 2011) for public access. This platform offers a wide selection of packages for different types of biological and experimental studies with a special emphasis on the standardization of metadata reporting. These packages follow the guidelines from the MIxS standards developed by the Genomics Standard Consortium (GSC) and adopted by the three partners of the International Nucleotides Sequencing Database Collaboration (INSDC) (Cochrane G, et al, Nucleic Acids Res, 44:D48-50, 2016) - National Center for Biotechnology Information (NCBI), European Bioinformatics Institute (EBI) and the DNA Data Bank of Japan (DDBJ). METAGENOTE then compiles, validates and manages the submission through an easy-to-use web interface minimizing submission errors and eliminating the need for submitting sequencing files via a separate file transfer mechanism. Conclusions METAGENOTE is a public resource that focuses on simplifying the annotation and submission process of data with its corresponding metadata. Users of METAGENOTE will benefit from the easy to use annotation interface but most importantly will be encouraged to publish metadata following standards and ontologies that make the public data available for reuse.

Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART.Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1-5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers.Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART.Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.

SummaryEnvironmental Enteric Dysfunction (EED) is an intestinal disease caused by malnutrition and infection that leads to malabsorption and stunting. EED is also associated with a reduced efficacy of oral vaccines. We show in a microbiota and diet-dependent model of EED that oral vaccine-specific CD4+ T cell responses fail in the small intestine but responses in the draining lymph node were unaffected. Accordingly, the number of immunosuppressive RORγT+FOXP3+ Tregs in the small intestine inversely correlated with the response to oral vaccination. Depletion of RORγT+FOXP3+ Tregs indicated that they were necessary for EED-associated inhibition of the vaccine response. Additionally, RORγT+FOXP3+ Tregs are important to regulate EED-associated inflammation as their depletion significantly worsened stunting. We have shown that EED-associated intestinal inflammation leads to a localized intestinal blockade of CD4 T cell immunity. These results support a modular model for immunity where tissue responses can be regulated independently of systemic immunity to prevent autoinflammation.

Summary Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

Changes in maternal immunity during pregnancy can result in an altered immune state, and as a natural perturbation, this provides an opportunity to understand functional interactions of the immune system in vivo. We report characterization of maternal peripheral immune phenotypes for 33 longitudinally sampled normal pregnancies, using clinical measurements of complete blood counts and major immune cell populations, as well as high parameter flow cytometry for 30 leukocyte antigens characterizing 79 cell populations, and monitoring of 1305 serum proteins using the SomaLogic platform. Cellular analyses characterized transient changes in T cell polarization and more persistent alterations in T and B cell subset frequencies and activation. Serum proteomic analysis identified a potentially novel set of 7 proteins that are predictive of gestational age: DDR1, PLAU, MRC1, ACP5, ROBO2, IGF2R, and GNS. We further show that gestational age can be predicted from the parameters obtained by complete blood count tests and clinical flow cytometry characterizing 5 major immune cell populations. Inferring gestational age from this routine clinical phenotyping data could be useful in resource-limited settings that lack obstetric ultrasound. Overall, both the cellular and proteomic analyses validate previously reported phenotypic immunological changes of pregnancy and uncover potentially new alterations and predictive markers.