bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential activity of innate and adaptive lymphocytes supports non-inflammatory gut microbial commensalism
Authors: Mao Kairui , Baptista Antonio , Bouladoux Nicolas , Martins Andrew J , Tamoutounour Samira , Davis Jacquice , Huang Yuefeng , Gerner Michael Y. , Belkaid Yasmine , Germain Ronald N 
Published: January 2023

Abstract
The mammalian gut is colonized by trillions of microorganisms termed the “microbiota”, which have a mutually beneficial relationship with their host. In normal individuals, the gut microbiota matures after birth to a state of balanced commensalism that is marked by the absence of adverse inflammation. Both innate lymphoid cells (ILCs) and antigen-specific conventional T cells contribute to containment and clearance of microbial pathogens. But how these two major lymphoid cell populations help shape the mature commensal (non-pathogenic) microbiome and maintain tissue homeostasis has not been determined. Using advanced multiplex quantitative imaging methods, here we show that in the absence of adaptive lymphocytes, IL-23 induced by specific commensal bacteria such as Segmented Filamentous Bacteria (SFB) persistently activates RORgt+ group 3 innate lymphoid cells (ILC3s) in the ileum to produce IL-22, which induces STAT3 activation in virtually all epithelial cells, contributing to production of molecules such as anti-microbial peptides that protect the tissue from microbial damage. The distinct roles of ILCs in handling gut microbes play out in normal mice during development. The pSTAT3 signature is absent after birth, which is followed by microbial colonization and strong ILC3 activation and an extensive epithelial pSTAT3 signature upon weaning. This innate immune activity is subsequently extinguished as adaptive CD4+ T cell immunity develops in response to the expanding commensal burden. Our findings provide new insights into how innate and adaptive lymphocytes sequentially operate during normal development to establish steady state commensalism.
IL-17 promotes intestinal IgA response to intestinal infection but does not affect memory B cell development
Authors: Huang Xiangsheng , Sun Mingming , Chen Feidi , Xiao Yi , Chen Liang , Yao Suxia , Cong Yingzi 
Published: January 2023

Abstract
Secretory IgA is the principal immunoglobulin found in intestinal track and plays a crucial role in maintanence of intestinal homeostasis. We have previously demonstrated that Th17 cells, which produce IL-17, IL-21 and IL-22, promoted intestinal IgA responses to microbiota. However, the mechanisms involved are still largely unknown. In current study, we investigated the roles of Th17 cells in regulation of intestinal IgA response to enteric pathogen infection. We showed that adoptive transfer of CBir1-specific Th17 cells, which are specific for immunodominant gut bacterial antigen CBir1 flagellin, promoted intestinal IgA in T cell-deficient TCRβxδ−/− mice, which is inhibited by the blockade of IL-17 and IL-21. To determine whether IL-17 regulates memory IgA B cell responses to intestinal infection, we infect wild type (WT) and IL-17R−/− mice with Citrobacter Rodentium, and C. Rodentium in the intestines, as well as fecal C. Rodentium-specific IgA and lamina propria IgA+ memory B cells were assessed. IL-17R−/− mice shows less efficiency in C. Rodentium clearance, in that while there were almost no bacteria at week 2 after infection in WT mice, significant amounts of C. Rodentium were still present in IL-17R−/− mice. Consistently, in IL-17R−/− mice C. Rodentium-specific intestinal IgA production was impaired compare with WT mice, and the memory IgA development was diminished after re-infection. However, there was no difference in lamina propria IgA+ memory B cells between WT and IL-17R−/− mice. Collectively, our data demonstrated that the IL-17 promotes intestinal IgA responses to intestinal infection, however, it does not affect memory IgA B cell development.
HVEM expression by innate lymphoid cells protects against enteric bacterial infection
Authors: Seo Goo-Young , Shui Jr-Wen , Takahashi Daisuke , Song Christina , Mikulski Zbigniew , Kim Pyeung-Hyeun , Cheroutre Hilde , Colonna Marco , Kronenberg Mitchell 
Published: January 2023

Abstract
Yersinia enterocolitica causes food-borne disease and targets the small intestine, in which ILC3 are the predominant ILC subset. Here we show that ILC3 are required for protection of mice from oral Y. enterocolitica, as mice lacking ILC3 were more susceptible and transfer of ILC to recipients was protective. IFNγ is a cytokine required for host defense from this pathogen, and while ILC in the small intestine did not increase in number they greatly increased IFNγ production after infection. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily (TNFRSF), is expressed by all intestinal ILC subsets. Mice with a deficiency of HVEM expression in RORγt+ ILC had a reduced steady-state IL-22 production, and in vitro HVEM could signal to ILC3 to stimulate IL-22 secretion. Moreover, following oral infection with Y. enterocolitica, mice with HVEM deficiency mediated by Rorc-cre showed reduced survival and increased bacterial translocation early after infection. Cytokines are known to induce ILC activation, but our results demonstrate a novel role for the cell surface receptor HVEM in regulating ILC3 cytokine production, both at steady state, and as a critical survival factor during acute infection.
Cell-intrinsic TLR4-dependent bone marrow lympho-myeloid distortions in obesity
Authors: Borghesi Lisa A , Liu Ailing , Chen Minhui , Kumar Rashmi , Stefanovic-Racic Maja , O’Doherty Robert , Ding Ying , Jahnen-Dechent Willi 
Published: January 2023

Abstract
Obesity compromises bone marrow (BM) progenitor function and the mechanistic underpinnings are just beginning to be established. Here we show that following 16 weeks of high fat diet, mice exhibit poor emergency hematopoiesis in a toll-like receptor 4 (TLR4)-dependent manner, and that adoptive transfer of obese BM to lean recipients restores rebound capability. Genes associated with a myeloid signature (c-fms, pu.1, ikaros) are enhanced and lymphoid signature (flt3, meis1, e47) reduced. The skewed lympho-myeloid outgrowth of discrete BM subsets is apparent by 6 weeks of high fat diet, earlier than is commonly recognized. Using mixed BM chimeras we demonstrate that obesity-associated subversion of lineage-c-kit+Sca-1- (LKSneg) precursors to the myeloid lineage and common lymphoid progenitors (CLP) to the B lineage depends on BM cell subset-autonomous TLR4. The endogenous TLR4 ligands responsible for BM dysfunction in obesity are unclear. Here, we show that exposure of lean mice to lipopolysaccharide (LPS) at levels similar to that observed in obesity recapitulates key aspects of BM lympho-myeloid disruption. Together, our results establish a mechanistic role for BM cell-intrinsic TLR4 early in obesity-driven BM dysfunction, and demonstrate the biological importance of one obesity-associated TLR4 ligand.
MiRNAs are required for embryonic development of Langerhans Cells
Authors: Martin Carly Elizabeth , Yao Yi , Mi Qing-Sheng , Zhou Li 
Published: January 2023

Abstract
Langerhans cells (LCs) are epidermal-resident dendritic cells that play important roles in skin immunity and tolerance. Recent fate-mapping studies have demonstrated that adult LCs derive predominantly from fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. However, the role of epigenetic regulations in embryonic development of LCs remains unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that negatively regulate gene expression of their mRNA targets. We and others recently reported that miRNAs are key players in regulating immune cell development and function, including LCs. To further study the role of miRNAs in LC ontogeny, we generated CSF1rCreDicerf/fKO mice in which miRNAs are deficient in myeloid lineage cells including LCs. As expected, the frequency of LCs was drastically reduced in Dicer KO adult mice. Interestingly, there was also a significant reduction (p=0.027) of epidermal LCs in Dicer KO embryos at E18.5, suggesting that miRNAs are crucial for embryonic development of LCs. Given the differential expression of miR-150 and miR-155 in embryonic LC development, we generated CSF1rCremiR-150f/fKI and CSF1rCremiR-155f/fKI mice in which expression of miR-150 and miR-155 is upregulated in LC-lineage, respectively. Surprisingly, neither strain caused defective LC development in fetal or adult epidermis. Overall, this is the first study to demonstrate that miRNAs are required for embryonic LC development. Furthermore, although overexpression of miR-150 or miR-155 is dispensable for LC ontogeny, the specific miRNAs responsible for proper LC development deserve to be further explored.
Control of B cell development and malignant transformation by microRNA-142
Authors: Wang Wei-Le , Magilnick Nathaniel , Reyes Estefany , Boldin Mark P 
Published: January 2023

Abstract
MicroRNA-142 (miR-142) is a versatile posttranscriptional regulator that plays a crucial role in the regulation of both innate and adaptive immune responses. Abrogation of miR-142 expression in mice results in a profound immunodeficiency that is characterized by hypoimmunoglobulinemia and failure to mount robust humoral immune responses to soluble antigen challenges. Paradoxically, miR-142−/− mice display a significant expansion of the B cell compartment due to the accumulation of immature and mature B lymphocytes. To better understand the role of miR-142 in B cell ontogenesis, we examined the early B cell development in miR-142−/− mice using the Hardy fraction analysis. We found that miR-142 deletion results in a significant increase in the frequency of the pro-B and large pre-B cells (Fractions B and C), while the pre-pro-B cell population (Fraction A) decreased. In contrast, miR-142 ablation had little effect on the frequency of small pre-B cell and immature B cell populations. Furthermore, our data suggest that the accumulation of pro-B and large pre-B cells in miR-142−/− bone marrow is linked to an increase in their survival capacity.
Because genetic lesions that disrupt control of B cell maturation frequently contribute to the malignant transformation of B cells, we decided to examine the role of miR-142 dysregulation in B cell lymphomagenesis. To address this question, we bred miR-142−/− mice with Eμ-myc transgenic mice that spontaneously develop a mix of pre-B cell and mature B cell lymphomas. We found that miR-142 haploinsufficiency dramatically accelerated lymphoma development in this mouse model. Collectively, our results establish miR-142 as an essential negative regulator of B cell maturation and lymphomagenesis.
E protein activity in DC precursors dictates the differentiation outcome of DC subsets.
Authors: Bajana Sandra Indiana , Thomas Kevin , Mengarelli Joni , Sun Xiao-Hong 
Published: January 2023

Abstract
Dendritic cells (DC) comprise plasmacytoid DC (pDC) and conventional DC (cDC) subsets; the latter is further separated into type 1 (cDC1) and type 2 (cDC2). These cells play a role in initiating and modulating immune responses. Their development is controlled by a network of transcription factors including E proteins consisting of E12, E47, HEB and E2-2, which share a basic helix-loop-helix domain mediating dimerization and DNA binding. Their activity is regulated by their antagonists, Id1-4. The balance between E and Id proteins regulates the transcription of E protein target genes. While E2-2 is essential for pDC differentiation and Id2 is indispensable for cDC1 formation, little is known about how the balance between E and Id proteins controls the early steps of the commitment of common DC precursors (CDP) to the diverse DC subsets. To address this, we used a mouse model that inducibly expresses a chimeric protein, ET2, which contains the DNA binding domain of Tal1 and the transactivation domains of E47. It can compete with Id proteins to bind endogenous E proteins and restore their DNA binding activity, thus increasing net E protein activity. Our data indicated that ET2 expression inhibited the differentiation of pDC and cDC2 subsets in vivo and in vitro. In contrast, cDC1 production was slightly elevated in steady state but dramatically increased in allergic reactions. Furthermore, we detected an augmented proportion of the newly identified cDC1 precursors and decreased representation of cDC2 precursors, suggesting E proteins skew CDPs toward the cDC1 lineage. These results are consistent with reports that E proteins activate IRF8 gene transcription. Further investigation is in progress to elucidate the molecular mechanisms.
Parainfluenza virus spread and clearance in a hematopoietic cell transplant model
Authors: Mostafa Heba , Vogel Peter , Baviskar Pradyumna , Russier Marion , Srinivasan Ashok , Russell Charles J 
Published: January 2023

Abstract
Parainfluenza viruses (PIV) are significant causes of morbidity and mortality in patients receiving hematopoietic cell transplant (HCT), particularly in the first 100 days post an allogeneic transplant. In the absence of effective therapeutic or preventive measures, it is critical to identify the immunological determinants that facilitate viral clearance that could be exploited for intervention, especially with respect to lower respiratory involvement. To study the dynamics of PIV infection in HCT host, we developed an allogeneic mouse model that we infect with a murine PIV. Specifically, we use a reporter Sendai virus that allows a daily, non-invasive bioluminescence imaging in living mice. HCT mice were infected shortly before transplant to study viral progression and clearance in the most critical period after transplant. Our data showed a marked prolongation of infection with a significant delay in clearance (21 days). The initiation of clearance correlated with a slight rebound in lymphocytes, which were mostly of the B type with more than 90% chimerism. Changing the initial site of infection by changing the infecting volume from 5 to 30 μL dramatically increased the lung signal, morbidity, and mortality. Treating the mice with Sendai-specific monoclonal antibodies significantly reduced the lung bioluminescence, morbidity, and prevented mortality. Overall, we developed a system that allows studying the correlation between different aspects of the immune system and PIV progression and clearance. Ongoing studies will determine the effect of manipulating the graft, including T cell enrichment versus depletion and the role of natural killer cells on Sendai virus infection.
TCF-1 Regulates Peripheral Treg Homeostasis
Authors: Yang Bi-Huei , Yuan Xiaomei , Dong Yi , Fu Wenxian 
Published: January 2023

Abstract
CD4+Foxp3+ regulatory T (Treg) cells are key players in preventing lethal autoimmunity and excessive inflammation. Based on their functional status, Treg cells can be distinguished into central (resting) and effector (activated) subsets. The homeostatic regulation between these two subsets is essential for Treg biology. However, what controls the dynamics between central and effector Treg cells remains poorly understood. We find that Wnt signaling transcription factor, TCF-1 plays a central role in regulating the differentiation from central to effector Treg cells. Although TCF-1 is crucial for T cell lineage specification, its expression is declined in a precisely-quantitative manner over the course of Treg development. Based on the expression of TCF-1, effector Treg cells can be further divided into two subsets. TCF-1neg subset is characterized as bona fide effector Treg cells. Transgenic modulation of TCF-1 alters the abundance of effector Treg cells. Our data suggest a two-step regulation of peripheral Treg homeostasis and TCF-1 play a critical role in this process.
Mucosal-associated invariant T cells respond to cutaneous microbiota
Authors: Constantinides Michael G , Linehan Jonathan L , Sen Shurjo , Shaik Jahangheer , Roy Sobhan , LeGrand Jess L , Bouladoux Nicolas , Adams Erin J , Belkaid Yasmine 
Published: January 2023

Abstract
The microbiome consists of a diverse array of commensal microorganisms that reside at barrier sites of the body and promote immune homeostasis through the release of microbial products, including derivatives of vitamin synthesis. Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize vitamin B2 (riboflavin) derivatives presented by the major histocompatibility class I-like molecule, MR1. MAIT cells are predominantly located in barrier tissues, where they represent a substantial population of non-classical T cells and provide an initial defense to pathogens through their rapid production of either IL-17A or IFNg. However, it remains to be determined whether commensals regulate the development and function of MAIT cells. Here we show that MAIT cells are present in murine skin at a high frequency and their homeostasis requires the microbiota, as these lymphocytes are nearly absent in germ-free animals. Furthermore, application of distinct human commensal bacteria to the skin of mice induces the proliferation of IL-17A-producing MAIT cells that exhibit a unique transcriptional profile. The induction of these cells occurs in a manner that is partially dependent on both antigen presentation and IL-23 signaling. Additionally, MAIT cells stimulated by the cutaneous microbiota provide heterologous protection against subsequent pathogenic challenges. This work identifies MAIT cells as the only cell population that is entirely dependent on the microbiota and reveals the mechanism by which these cells respond to the commensal microbial community. Due to the high frequency of MAIT cells in human skin, these observations suggest that modulation of the skin-resident bacteria may have clinical applications.
Deficiency in vasoactive intestinal peptide signaling causes compositional and functional changes in mouse fecal microbiota
Authors: Bains Manpreet , Laney Caleb , Schuh Jane M , Dorsam Glenn P 
Published: January 2023

Abstract
By 2030, half the human population will be obese contributing to diabetes, cancer and cardiovascular disease. The gut peptide, vasoactive intestinal peptide (VIP) that acts as a regulator of innate and adaptive immunity, is elevated in obese humans. VIP mediates immunity changes through binding two receptors, called VPAC1 and VPAC2. Unfortunately, the pathways linking VIP signaling to obesity are not known. We hypothesized that defective VIP signaling would have an anti-obesity effect by lowering the gut firmicutes/bacteroidetes (f:b) ratio. To this end, knockout mice deficient for VIP, VPAC1 or VPAC2, were used to collect 16S rRNA reads from fecal samples. Operational taxonomic units for each strain were compared against each other to determine changes in bacterial taxa. Moreover, differences in gene functions were analyzed using PICRUSt. These data revealed a significant decrease in the f:b ratio for mice deficient in VIP and VPAC2 compared to wild type controls. Heterozygous and homozygous littermates for the VIP mutation showed the greatest reduction in fecal bacterial richness and clustered differently when compared phylogenetically to wild type or VIP receptor knockout strains. Metabolome predictions indicated that genes regulating the circulatory system and cardiovascular disease were consistently altered in mice deficient for VIP or its two receptors. In summary, deficiency in the VIP signaling axis significantly alters the gut microbiota and microbiome.
The role of gut microbiota in shaping the immune response in relapse-remitting and chronic-progressive mouse models of multiple sclerosis
Authors: Gandy K. Alexa Orr , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
In this study, we used a mouse model of multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), to evaluate the role of gut microbiota in modulating T helper cell function in chronic-progressive (CP) versus relapse-remitting (RR) forms of the disease. We hypothesized that encephalitogenic T cell function in RR-EAE and CP-EAE is differentially shaped by gut microbiota. Metagenomic sequencing of the variable V4 region of the prokaryotic 16S ribosomal RNA gene present in feces derived from naïve mice and mice exhibiting CP-EAE or RR-EAE revealed significantly diverse microbial populations, which may be responsible for differing disease courses. Specifically, the order Bacteroidales was dominantly represented by RR-EAE mice, with very little or no detection in naive or CP-EAE mice, suggesting a potential role for bacteria in this order in shaping tolerant or remittance-favoring conditions. Additionally, Akkermansia and rc4-4, of phyla Verrucomicrobia and Firmicutes, respectively, were identified specifically in CP-EAE, suggesting a potential pathogenic or pro-inflammatory role for bacteria belonging to these taxa, at least in the context of EAE. We performed qRT-PCR in order to test the validity of the sequencing findings, as well as used a gas chromatograph configured with flame-ionization detectors to evaluate short chain fatty acids from cecal flushes. The current study implies a role for gut microbiota in differentially shaping the immune response in models of RRMS and CPMS. Information regarding tolerance–promoting or –inhibiting conditions shaped by gut bacteria can be harnessed for the potential development of therapies for diseases possessing important inflammatory components.
Dose dependent effect of BAFF receptor specific mAb-siRNA conjugate in experimental myasthenia
Authors: Huda Ruksana 
Published: January 2023

Abstract
We investigated potential therapeutic effect of a conjugate of BAFF receptor specific- monoclonal antibody and short interference RNA in a mouse model of myasthenia gravis (EAMG). We found that at high dose, conjugate treatment caused significant accumulation of Fas expressing CD19+/ B220+ cells and increased type 1 interferon in lymph nodes. Low dose did not induce FAS expression but caused marked BAFF receptor deficiency in lymph nodes that was further associated with improved MG symptoms. Conjugate treatment, however, did not reduce the levels of autoantibody. Our findings, thus, reveal a previously undocumented, dose dependent, immunomodulatory distant effect resulting from BAFF receptor specific mAb-siRNA conjugate treatment in an in vivo model of autoimmune disease.
RNA binding protein HuR is required for efficient function but not generation of Foxp3+ Treg
Authors: Ellis Jason S , Ridenhour Suzanne , Glascock Jacqueline , Atasoy Ulus 
Published: January 2023

Abstract
The RNA-binding protein (RBP) HuR (Elavl1) controls differentiation of CD4+ T cells into Th2 and Th17 helper subsets through regulating transcript stability of multiple subset specific targets. We recently generated dLck-Cre HuRfl/fl mice, in which HuR is conditionally knocked out in T cells late during thymic development. There was a 5:1 skewing toward HuR sufficient Treg in these mice, though there was only a small reduction in the total number of peripheral Treg compared to controls. More interestingly, HuR deficient naïve CD4+ T cells from these mice are less susceptible to Treg polarization than control HuR competent T cells and fail to upregulate Foxp3 following activation. We conditionally ablated HuR in Tregs (Foxp3YFP-Cre HuRfl/fl mouse) (HuR KO). These mice have significant failure to thrive in both hemizygous Foxp3YFP-CreHuRfl/fl males (39% weight reduction) and homozygous Foxp3YFP-Cre/YFP-Cre HuRfl/fl females (30% reduction). However, heterozygous Foxp3YFP-Cre/WT HuRfl/fl females have normal weight gain over time. Heterozygous HuR KO females also have a significant shift in the ratio of HuR− Treg to HuR+ Treg indicating a possible survival bias toward Treg expressing WT levels of HuR. Both male and female HuR KO mice have features of scurfy mice, including alopecia and stippled tails. This coincides with multiorgan inflammation which includes lung, skin, stomach and liver. Additionally, naïve HuR KO mice have significantly reduced peripheral Treg and increases in Foxp3− effector T cells with an activated phenotype. Together, these data suggest HuR is critical for effective Treg function and generation of iTreg.