bluuebunny/crossref_metadata_2025_split huggingface dataset:
IRF4-dependent DCs promote the establishment of CD8+ T cell memory during influenza infection.
Authors: AINSUA-ENRICH EROLA , Hatipoglu Ibrahim , Kadel Sapana , Turner Sean , Paul Jinny , Kovats Susan 
Published: January 2023

Abstract
The transcription factor IRF4 governs the development and function of CD11b+ dendritic cells (DCs). To determine the role of IRF4-dependent DCs in influenza infection, we compared responses of wild-type and CD11c-cre-Irf4f/f(KO) mice. The KO mice lack one lung-resident CD11b+ DC subset, and the other DC subsets lack IRF4. Upon infection with A/PuertoRico/8/34 virus, KO lung DCs contained increased IL-12 and reduced IL-10 RNA, which correlated with elevated numbers of CD103+ lung migratory DCs in the mLN. Consistent with this, KO mice showed greater numbers of T-bet+ and IFNg+ influenza antigen-specific CD8+ and CD4+ T cells, reduced numbers of Foxp3+ T regulatory cells, and decreased numbers of CD8+ T memory precursor cells. These altered effector T cell populations in KO mice impacted the memory T cell response to influenza virus. Numbers of virus-specific lung resident memory CD8+ T cells were significantly reduced in KO mice. Upon challenge with heterosubtypic virus, KO mice showed deficient expansion of virus-specific IFNγ+ CD8+ T cells. Taken together, these data show that KO mice mount a stronger antiviral T cell response upon primary infection but then have a weaker CD8+ T cell memory response to heterosubtypic virus. This supports the hypothesis that during influenza infection, the functional responses of IRF4-dependent DCs lead to increased differentiation of CD8+ memory precursor T cells and numbers of lung resident CD8+memory T cells.
Endogenous Secondary TCRs Promote Homeostatic Advantage Via Recognition of Self-Antigens
Authors: Balakrishnan Amritha , Jama Burhan , Morris Gerald P 
Published: January 2023

Abstract
Our laboratory studies how non-thymically selected secondary TCRs contribute to the T cell repertoire. We have previously demonstrated that peripheral T cells naturally expressing 2 TCRs have increased response to autoantigens. We hypothesized that this could promote homeostatic proliferation of T cells expressing 2 TCRs, which may cause autoimmune risk. To examine secondary TCRs in homeostasis, we performed competitive transfers of CFSE-labeled T cells from B6.Ly5.1 and B6.TCRα+/−.Thy1.1 (lacking secondary TCRs) into irradiated B6 recipients. T cells injected at a 1:1 ratio demonstrated a disadvantage for TCRα+/− T cells in lymphopenia-induced proliferation (LIP), with TCRα+/−/wt donor cell ratios of 0.6±0.1 at 8 d after transfer and 0.5±0.4 at 28 d after transfer. T cell population skewing resulted from increased proliferation of wild-type cells. The homeostatic advantage of secondary TCRs was less in chronic LIP (cLIP) (transfer into TCRα-knockout mice), with TCRα+/−/wt donor cell ratios of 0.8±0.3 at 8 d after transfer and 0.7±0.3 at 28 d after transfer. There was no difference between wt and TCRα+/− T cells in proliferative response to stimulation via anti-CD3/CD28, nor were differences observed for expression of CD3, CD5, or CD127. LIP and cLIP depend on signaling through the TCR, though reactivity to self-antigens is thought to drive LIP as opposed to endogenous antigens from commensal microflora in cLIP. Our results suggest that the advantage for secondary TCRs in homeostatic expansion reflects increased ability to interact with self-pMHC antigens. Current effort is focused to understand how this affects protective and autoreactive peripheral T cell repertoires during aging or iatrogenic lymphopenia.
The Intersection of Immune Responses, Microbiota and Pathogenesis in Giardiasis
Authors: Fink Marc Y , Maloney Jenny Grace , Keselman Aleksander M , Li Erqiu , Singer Steven M 
Published: January 2023

Abstract
Infection with the protozoan parasite, Giardia, can produce a range of symptoms including diarrhea, severe cramps, and nutrient malabsorption. Our lab and others have previously indicated that immune responses can contribute to pathogenesis. It has also been reported that intestinal microbiota can affect the ability of the parasite to colonize laboratory mice. Our goal was to determine if intestinal immune cells were activated following infection and how the microbiota interacted with intestinal immune responses.
Wild-type or CCR2 deficient mice were treated with a cocktail of antibiotics and infected with the GS strain. Control mice were not treated with antibiotics and/or were not infected. Changes in the intestinal microbiome and immune responses were determined using 16S sequencing and flow cytometry of isolated lamina propria and intraepithelial lymphocyte populations, respectively. Sucrase activity was also measured in mucosal lysates.
Mice treated with antibiotics or infected with Giardia exhibited shifts in their intestinal microbiomes. With or without antibiotics, we observed an increase in the frequency of CD4+ T cells in the lamina propria at day 7 post-infection. We also observed an increase in macrophage populations and activated CD8+ T cells, but only in mice not treated with antibiotics. Macrophage populations increased in wild-type and CCR2-deficient mice, and EdU labeling suggested in situ proliferation of resident macrophages. Finally, sucrase deficiency correlated with activation of CD8+ T cells.
Together these data indicate that the intestinal microbiota contribute to immune cell activation during infections and suggest that the microbiota may contribute to different infection outcomes.
Progression of experimental autoimmune encephalomyelitis (EAE) increases manganese superoxide dismutase (MnSOD) protein in the mitochondria of the mouse renal cortex
Authors: Zhou Xiaoming , Packialakshmi Balamurugan 
Published: January 2023

Abstract
Sodium has been implicated in the high NaCl diet-induced exacerbation of EAE. The kidney cortex is the primary site for regulating Na homeostasis. Reabsorption of Na by the cortex absolutely relies on the ATP-dependent Na,K-ATPase. Our previous studies demonstrated that the progression of EAE increases the Na,K-ATPase activity in the cortex even under normal salt intake. Mitochondrial respiration not only generates ATP, but also produces reactive oxygen species (ROS). As MnSOD is the first line of defense against the harmful effect of mitochondrial ROS, the present study analyzed whether EAE had any effects on MnSOD. Progression of EAE from mild to severe stage increased total MnSOD protein by 38% and had no significant effect on CuZnSOD protein. This effect was not explainable solely by the illness-induced reduction of water or food intake. Further analyses reveals that severe EAE increased mitochondrial MnSOD protein by 47%, Na,K-ATPase beta1 subunit protein by 64% with a concomitant increase of mitochondrial function as measured by the complex II activity and protein level of cytochrome oxidase 4, a major component of complex IV. Activation of Na,K-ATPase with two mechanistically different reagents, monensin and dexamethasone, simulates the effect of EAE on MnSOD protein in HEK293 cells. Fluorescent microscopic study showed that monensin and dexamethasone increased ROS in HEK293 cells, and this effect was inhibited by 400 U/ml catalase. Similarly, catalase also erased the effects of monensin and dexamethasone on MnSOD protein. In conclusion, progression of EAE increases mitochondrial MnSOD protein in the kidney cortex, likely due to the ROS produced during respiration to meet the demands of ATP for the Na,K-ATPase.
Selective inhibition of NF-kB inducing kinase (NIK) is therapeutically efficacious in IFNα-accelerated lupus nephritis prone mice
Authors: Brightbill Hans D , Suto Eric , Blaquiere Nicole , Ramamoorthi Nandhini , Sujatha-Bhaskar Swathi , Gogol Emily , Castanedo Georgette , Jackson Benjamin , Haller Susan , Lesch Justin , Bents Karin , Everett Christine , Kohli Pawan Bir , Linge Sandra , Christian Laura , Barrett Kathy , Jaochico Allan , Berezhkovskiy Leonid M , Fan Peter W , Veliz Kelli , Townsend Michael , DeVoss Jason , Johnson Adam , Godemann Robert , Lee Wyne P , Austin Cary D , McKenzie Brent , Hackney Jason A , Crawford James J , Staben Steven , Ismaili Moulay Hicham Alaoui , Wu Lawren C , Ghilardi Nico 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is often considered a disease driven by autoreactive B cells and anti-nuclear antibodies. However, therapeutic targeting of B cells, for example through BAFF blockade, has been only partially effective in SLE. NF-kB Inducing Kinase (NIK) mediates non-canonical NF-kB signaling downstream of disease relevant TNF family members, such as BAFF, TWEAK, CD40, and OX40. We hypothesized that NIK inhibition might be more efficacious than BAFF blockade in lupus, and therefore generated a highly selective and potent small molecule inhibitor (SMI) of NIK to test this hypothesis. In cellular assays, this molecule inhibits non-canonical NF-kB signaling downstream of multiple TNFRSF family members. In order to differentiate the effects of NIK inhibition and BAFF blockade in vivo, we compared NIK inhibition with BAFF blockade in the context of NZB/W F1 lupus prone mice. As predicted, NIK inhibition recapitulated the pharmacological effects of BAFF blockade. Furthermore, NIK inhibition, but not BAFF blockade, affected T cell parameters in the spleen and pro-inflammatory gene expression in the kidney, the latter of which is partly attributable to TWEAK signaling. Finally, NIK inhibition resulted in improved survival, ameliorated renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition affects multiple disease-relevant pathways and may therefore have superior efficacy compared to BAFF inhibition in SLE.
Prostaglandin E2 receptor (EP2): a novel target to attenuate excessive bone loss during autoimmune arthritis
Authors: Ignatowicz Aleksandra P , Patterson Daryllynn C , Mula Ramanjaneya V R , Dingledine Raymond J , Ganesh Thota , Shashidharamurthy Rangaiah 
Published: January 2023

Abstract
Prostaglandin-E2 receptors (sub type EP2) are known to be activated during various autoimmune inflammatory disorders including rheumatoid arthritis (RA) and may play an essential role in exacerbating the bone damage during RA. Recently, we have reported that EP2 antagonists inhibited pro-inflammatory cytokine responses at the transcriptional level using murine monocytic cell line and observed that EP2 antagonists attenuate the upregulation of several inflammatory mediators in vitro. It has been shown that EP2 gene deletion in mouse cultures impairs osteoclast formation. Herein we investigated the anti-osteoclastogenic activity of recently discovered EP2 antagonists using an in vitro osteoclastogenesis model using mouse monocytic cell line (RAW264.7 cells). We observed significantly increased size and number of osteoclasts by both PGE2 and butaprost (selective EP2 agonist) compared to receptor activator of nuclear factor kappa-B ligand (RANKL) alone treated cells. We did not observe significant difference in number of osteoclasts between PGE2 and butaprost. In addition, 10μM concentration of various EP2 specific antagonists (TG8-4, TG4-155 and TG6-129) inhibited RANKL-induced osteoclast formation. Western blot analysis revealed that EP2 antagonists decreased the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are the master regulators of osteoclastogenesis. These data indicates the direct effect of EP2 antagonists on bone cells in preventing the severe bone damage implying EP2 receptors play a major role during osteoclast formation, thus EP receptors should be explored as a therapeutic target to blunt the excessive bone loss during arthritis.
Transcriptome analysis reveals persistent effects of neonatal diet on the ileum gene expression in porcine neonates
Authors: Saraf Manish Kumar , Chen Celin , Bowlin Anne Kidd , Dawson Harry , Badger Thomas M , Yeruva V. Laxmi 
Published: January 2023

Abstract
Mechanism(s) underlying long-lasting effects of human breast milk (HBM) on gut development and immune function have not been investigated. To differentiate between HBM and formula diet’s persistent effect on gene expression of a small intestine, piglets (n=15/group) were fed either HBM or dairy-based formula (FM) from postnatal day 2 to 21, followed by a soy free pig wean diet until day 51. Relative to HBM-fed, FM-fed had heavier small intestine (436±15.3 vs 362±45 g, p&lt;0.05) but no change in the length. Transcriptome analysis revealed that the identified genes associated with cytokines (4↑, 9↓; i.e. CXCL8↓), Wnt (2↑, 9↓; CDHR2↓), gonadotropin releasing hormone receptor (1↑, 10↓; PRLR↓), EGF receptor (1↑, 7↓; CBL↓), cadherin (7↓; FRK↓) and endothelins (7↓; PRKG2↓) signaling were differentially expressed (2–5 fold) in ileum (IL) of FM-fed relative to HBM-fed. Moreover, the genes involved in biological processes such as cellular (84↑, 138↓; 2–12 fold), metabolic (71↑, 104↓; 2–17 fold), immune (14↑, 27↓; 2–10 fold) and developmental (16↑, 40↓ genes; 2–6.8 fold) were differentially expressed in IL of FM-fed relative to HBM-fed. Genes associated with T- (BRAF) and B-cell (BRAF, ITPR3 and FRK) activation were also decreased in IL of FM-fed relative to HBM-fed. NK, B and T-reg cells populations were reduced in mesenteric lymph nodes of FM-fed relative to HBM-fed. In summary, the data suggest a persistent effect of FM and HBM diets on small intestine and diet-driven changes in specific pathways of a small intestine. HBM may regulate these pathways to favor the gut development and immune function. However, FM may not harmonize it well and thereby delay the physiological process. Microbiome role is being evaluated to understand a specific mechanism.
Gut microbiota as a source of signals that trigger spontaneous ocular autoimmunity.
Authors: Salvador Ryan S. , Horai Reiko , Tang Jihong , Zárate-Bladés Carlos , Jittayasothorn Yingyos , Itoh Kikuji , Umesaki Yoshinori , Caspi Rachel R 
Published: January 2023

Abstract
Autoimmune uveitis, a major cause of blindness, is thought to be driven by T cells specific for unique retinal antigens that have been activated and acquired the ability to cross the blood-retinal barrier. However, it is unknown where and how they first become activated. The R161H mouse expresses a transgenic TCR specific for the retinal protein IRBP and develops spontaneous uveitis with 100% incidence, permitting to study natural triggers of disease. Retina-specific T cells were activated in the intestine of specific-pathogen-free (SPF) R161H mice. Elimination of gut commensals by oral treatment with antibiotics (ABX) or by rearing under germ-free conditions (GF) significantly attenuated uveitis and reduced Th17 cells in the gut lamina propria. Bacteria-rich extracts of intestinal contents from SPF, but not GF or ABX mice, activated retina-specific T cells in vitro, and R161H T cells signaled through the clonotypic TCR in the gut in vivo, suggesting a role for gut microbiota as a source of stimulating signals for retina-specific T cells. To dissect the contribution of adaptive vs innate microbial signals, gnotobiotic studies were performed: GF R161H mice exposed to SPF conditions developed full-blown uveitis, but mono-colonization with segmented filamentous bacteria (SFB) or a Turicibacter strain (T. H121) only partially restored disease. Unlike intestinal extracts from SPF mice, extracts from monocolonized mice failed to activate R161H T cells in vitro, suggesting lack of “antigen” activity, but SFB (not T. H121) restored gut Th17-producing cells, indicating presence of “adjuvant” activity. Thus, microbial-derived adaptive “antigen” and innate “adjuvant” signals are both required for full development of uveitis.
Paneth Cell Specific Lysozyme Regulates Intestinal Mucosal Immune Response by Shaping Gut Microbiota Landscape
Authors: Yu Shiyan , Douard Veronique , Edelblum Karen L. , Laubitz Daniel , Zhao Yanlin , Kiela Pawel R , Yap George S , Gao Nan 
Published: January 2023

Abstract
Paneth cells produce antimicrobial proteins such as lysozyme and cytokines to interact with gut microbiota and mucosal immune system respectively, maintaining delicate mucosal immune homeostasis. Abnormalities in lysozyme expression or intracellular distribution have been cataloged in patients with inflammatory bowel disease (IBD) and mouse IBD models. However, it is unclear whether these defects are simply the consequences of IBD pathogenesis or they may also contribute to disease progression. To explore the role of Paneth cell lysozyme in such a microbe-friendly environment, we derived two mouse models: Paneth cell Lyz1 knockout (Lyz1KO) and gut epithelial Lyz1 overexpression (Villin-Lyz1). Using these two models, we performed fecal 16s rRNA sequencing and found that the abundance of several mucolytic bacteria (e.g. D. formicigenerans and R. gnavus) was increased in Lyz1KO mice but decreased in Villin-Lyz1, as confirmed by species specific qPCR. In addition, we confirmed that lysozyme could inhibit the growth of D. formicigenerans and R. gnavus in vitro. Interestingly, the number of goblet and tuft cell in Lyz1KO mice was increased compared to that in wildtype littermates. In line with this, type 2 cytokines (e.g. Il25 and Il13) were elevated in Lyz1KO mice. Antibiotics cocktail treatment rescued goblet and tuft cell hyperplasia, suggesting altered gut microbiota landscape is a critical factor inducing goblet and tuft cell hyperplasia. Consistently, disruption of intestinal type 2 immunity axis by anti-CD90.2 or anti-Il13 neutralizing antibody also ameliorated goblet and tuft cell hyperplasia. Taken together, our findings suggest lysozyme modulates intestinal type 2 immune response via shaping gut microbiota landscape.
Microbial and Maternal Factors Control the Development of RORγt+ Regulatory T Cells Promoting Durable Tolerance and Preventing Allergy
Authors: Knoop Kathryn A , McDonald Keely , Gustafsson Jenny , Hogan Simon P , Elson Charles O , Tarr Philip I , Newberry Rodney D 
Published: January 2023

Abstract
Mounting evidence emphasizes the importance of exposure to food allergens and gut microbes in early life to promote tolerance and reduce the risk of food allergy. Indeed the NIAID recently recommended early introduction of dietary peanut to reduce peanut allergy in at risk children. The mechanisms promoting tolerance during early life are incompletely understood, but potentially relate to a population of long-lived RORγt+ inducible regulatory T cells (iTregs) which prevent the development of food-specific Th2 responses throughout life. The optimal time for exposure to environmental antigens for the development of these RORγt+ iTregs, where in the gut protective exposures occur, and how the immune system’s contact with these antigens is controlled in early life remain unknown. We identified a window of time in early life in which luminal antigens are shunted to the colonic lamina propria (LP) and delivered to colonic LP antigen presenting cells by goblet cell-associated antigen passages (GAPs), correlating to an expansion of colonic LP RORγt+ iTregs. GAP formation was regulated by goblet cell sensing of breast milk epidermal growth factor and the blooming gut microbiota. Disruption of the gut microbiota or GAP formation and antigen delivery during early life abrogated tolerance to dietary antigens, decreased RORγt+ iTregs, and induced a skewing of the immune system toward systemic Th2 (allergic) responses. We propose the gut microbiota, in concert with maternal factors, control antigen delivery and the induction of RORγt+ iTregs during infancy. These mechanisms allow for proper education of the immune system against reaction to dietary and microbial antigens, a process that then suppresses inappropriate Th2 responses later in life.
GPR43 mediates microbiota metabolite SCFA induction of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3
Authors: Chen Feidi , Zhao Ye , Huang Xiangsheng , Chen Liang , Sun Mingming , Yao Suxia , Xiao Yi , Cong Yingzi 
Published: January 2023

Abstract
As a critical component in maintaining intestinal homeostasis, intestinal epithelial cells (IEC) are known to tune gut microbiota via antimicrobial peptides (AMP) production. In return, microbiota has been reported to regulate IEC expression of AMPs, including RegIIIg and certain defensins. The underlying mechanisms are, however, still not completely understood. The present study attempted to address the novel pathways by which gut microbiota regulates IEC expression of AMP as a way to contribute to intestinal homeostasis. We found that the mice with deficiency of GPR43, a receptor for short chain fatty acids (SCFA), the metabolites of gut microbiota, have lower expression of RegIIIg and b-defensins 1, 3, and 4 in IECs compared to that of WT mice. Oral feeding with SCFA promoted IEC production of both RegIIIg and defensins in mice. Moreover, ex-vivo culture of enteroid revealed that SCFA induction of IEC RegIIIg and b-defensins production is GPR43-dependent. Mechanistically, SCFA activated mTOR and STAT3 in IECs. Knockdown of either mTOR or STAT3 impaired SCFA-induced AMP production. Collectively, our data revealed that microbiota-derived SCFA promote IEC production of both RegIIIg and b-defensins, which is through GPR43 and mediated by mTOR and STAT3 pathways.
Vitamin A deficiency impacts acquisition, but not expression, of autoimmunity to the neuroretina
Authors: Horai Reiko , Zhou Ru , Bing So Jin , Wloka Kaska , Chen Jun , Silver Phyllis , Jittayasothorn Yingyos , Caspi Rachel R 
Published: January 2023

Abstract
Vitamin A (VitA) and its derivative retinoic acid (RA) are essential for immunological responses. Acquisition of effector responses is impeded in VitA-deficient (VAD) mice, but little is known about maintenance and expression of previously acquired effector function in the VAD environment, or its impact on progression of autoimmune diseases. We examined this using two models of uveitis: experimental autoimmune uveitis (EAU) induced by active immunization and spontaneous uveitis in retina-specific T cell receptor transgenic (R161H) mice, and in the model of experimental autoimmune encephalomyelitis (EAE). VAD was induced by dietary lack of VitA from before birth, or by daily injections of a pan-RA receptor inhibitor BMS493 in adult mice fed with standard diet. VAD mice were essentially resistant to induction of EAU or EAE and displayed impaired effector T cell responses. Defective priming/acquisition of effector function by VAD T cells was also evident in vitro. Interestingly, however, effector T cells primed in a VitA-sufficient environment were able to function in VAD recipients and induced EAU. Furthermore, spontaneously uveitic R161H mice fed with VAD diet, in which priming of pathogenic T cells occurs before onset of full VitA deficiency, appeared to develop unreduced or even exacerbated spontaneous uveitis compared to VitA-sufficient R161H mice. We conclude that although priming of naïve T cells in the VAD environment is defective, effector function acquired under VitA-sufficient conditions is maintained and can be expressed under VAD conditions. Because dietary lack of VitA is rarely profound and may be seasonal, our findings may shed light on immunity and autoimmunity in geographical regions where dietary VitA is limiting.