bluuebunny/crossref_metadata_2025_split huggingface dataset:
T cell intrinsic Nod2 controls Th17 immunity to Candida albicans infection
Authors: Koney Kylie , Lashley Sydney J , Lee Ellen J , Vance Emily E , Philpott Dana J , Dugan Jae W , Davey Michael M , Rosenzweig Holly L , Napier Ruth J 
Published: January 2023

Abstract
We recently discovered a role for Nod2 within T cells in controlling Th17-immunity, such that deletion of Nod2 exacerbated experimental autoimmune arthritis and uveitis. Protection against opportunistic Candida albicans infection relies on intact Th17-responses. Thus, we considered whether the T cell intrinsic Nod2 might control antifungal Th17 responses at the cost of increasing host susceptibility to autoimmunity. Nod2−/− mice infected with 105 (LD50) Candida albicans had increased survival and reduced fungal burden in the kidney within 24–72 h post-infection, suggesting a critical role for Nod2 in C. albicans immunity. Rag−/− mice reconstituted with Nod2fl/fl/CD4-cre CD4+ T cells and infected with C. albicans had decreased fungal burden compared to control CD4-Cre T cell recipients, and IL-17 depletion reverted the phenotype. After 48h infection, Nod2fl/fl/CD4-cre CD4+ T cells in the kidney had increased activation (CD69), increased proportion of T effector cells, and decreased Tregs compared to controls, suggesting endogenous Nod2 negatively regulates fungal-triggered Teff/Th17 cell responses. We next asked how Nod2 might function in SKG mice that are genetically susceptible to arthritis. Whereas Nod2−/− SKG mice developed an exacerbated form of arthritis compared to Nod2+/+ SKG controls, these same mice cleared C. albicans infection better than Nod2+/+ SKG mice. Cumulatively our data indicate a critical role for T cell intrinsic Nod2 in antifungal Th17 immunity. Given these studies we posit that human NOD2 genetic variants may offer enhanced ability to fight fungal infection via a T cell intrinsic mechanism, at the cost of triggering autoimmunity.
Supported by grants from VA (CDA-2 IK2BX004523 and Merit I01BX002180) and NIH (R01 EY025250).
IL-27 signaling promotes Th1 responses and is required to inhibit fungal growth in the lungs during repeated exposure to Aspergillus fumigatus
Authors: Strickland Ashley , Sun Donglei , Sun Peng , Chen Yanli , Liu Gongguan , Shi Meiqing 
Published: January 2023

Abstract
Aspergillus fumigatus is an opportunistic fungal pathogen that causes a wide spectrum of diseases in humans, including life-threatening invasive infections as well as a number of hypersensitivity respiratory disorders. Disease prevention is predicated on the host’s ability to clear A. fumigatus from the lungs while also limiting inflammation and preventing allergic responses. IL-27 is an important immunoregulatory cytokine, but its role during A. fumigatus infection remains poorly understood. In contrast to most infection settings showing that IL-27 is anti-inflammatory, here we report that this cytokine plays a proinflammatory role in mice repeatedly infected with A. fumigatus. We found that repeated exposure of mice to A. fumigatus led to significantly enhanced secretion of IL-27 in the lung. Genetic ablation of IL-27 receptor alpha (IL-27Rα) in mice resulted in significantly higher fungal burdens in the lung during repeated exposure to A. fumigatus. The increased fungal growth in IL-27Rα−/− mice was associated with reduced secretion of IL-12, TNF-α and IFN-γ, diminished T-bet expression, as well as a reduction in CD4+ T cells and their activation in the lung, demonstrating that IL-27 signaling promotes Th1 immune responses during repeated exposure to A. fumigatus. In addition, infected IL-27Rα−/− mice displayed reduced accumulation of dendritic cells and exudate macrophages in the lung with lower expression of MHC class II on these cells and had less M1 macrophage activation. Taken together, this study suggests that IL-27 drives type 1 immunity and is indispensable for inhibiting fugal growth in the lungs of mice repeatedly exposed to A. fumigatus, highlighting a protective role for this cytokine during fungal infection.
Supported by NIH (AI131219, AI131905)
Gut microbiota-reactive IgG regulates gut microbiota development and immunity against enteric pathogens in early life
Authors: Amir Mohammed , Sanidad Katherine , Ananthanarayanan Aparna , Zhang Lingzhi , Shiland Nicholas , Inohara Naohiro , Nunez Gabriel , Zeng Melody 
Published: January 2023

Abstract
The gut microbiota elicits antigen-specific IgG at steady state that cross-reacts to pathogenic Gram-negative Enterobacteriaceae to confer protection against systemic infection. The role of these IgG antibodies in the development of gut microbiome and immunity against enteric pathogens in early life, however, remains largely undefined. In this study, we demonstrate that gut microbiota-induced maternal IgG is transferred to the neonatal gut through maternal milk via the neonatal Fc receptor and confers critical protection by inhibiting colonization and attachment of C. rodentium to the mucosa in the neonatal gut. Enhanced neonatal immunity against oral C. rodentium infection was observed following maternal immunization with a gut microbiota-derived IgG antigen, outer-membrane protein A (OMP-A), or induction of protective IgG antibodies in germ-free mice after reconstitution with IgG-inducing gut bacteria. Furthermore, we generated a mouse model with complete deficiency in all IgG isotypes. IgG-deficient neonatal mice exhibited increased susceptibility to C. rodentium infection, altered gut microbiome and increased numbers of intestinal IL-17-producing γδ T cells driven by the gut microbiome at steady state. The altered gut microbiome persisted into adulthood in IgG KO mice and contributed to increased disease severity in DSS-induced colitis. Taken together, our studies have defined critical roles for gut microbiome-induced IgG antibodies in shaping the gut microbiome and immunity against Gram-negative enteric pathogens from early life to adulthood.
Education of uterine natural killer cells by maternal MHC drives fetal growth
Authors: Depierreux Delphine M , Kiekbush Jens , Shreeve Norman , Sharkey Andrew , Hawkes Delia , Colucci Francesco 
Published: January 2023

Abstract
Maternal uterine natural killer (uNK) cells, in partnership with fetal trophoblast cells, regulate physiological vascular changes in the uterus of pregnant women and mice. These vascular changes are necessary to build the placenta and sustain fetal growth. NK cell functions, in the uterus and elsewhere, are modulated by NK cell education, a quantifiable process that determines cellular activation thresholds. This process relies largely on interactions between self-MHC class I molecules and inhibitory NK cell receptors but its physiological importance has remained largely elusive.
NK cell education during pregnancy is unique because uNK cells are exposed to both maternal and fetal MHC-I molecules. Here, we set out to answer the question of how uNK cell education or missing-self recognition affect their function and, ultimately, fetal growth.
Using combinations of MHC-sufficient and -deficient mice, we show that maternal and not fetal MHC regulates uterine NK cell education in mice. MHC-deficient dams produce more growth-restricted fetuses, even when the fetuses themselves express self-MHC. We also show that, while peripheral NK cells reject bone marrow cells according to the established rules of missing-self recognition, uNK cells educated by maternal MHC do not reject fetuses that miss self-MHC and these fetuses grow to their full potential.
Our data shed light on the physiological importance of uNK cell education: by getting to know self, the maternal immune system sets up uNK cells to participate to the womb tissue homeostasis and to contribute to reproductive success.
This work was supported by the Cambridge NIHR BRC Cell Phenotyping Hub and by grants from the Wellcome Trust (094073/Z /10/Z), the MRC (MR/P001092/1) and the Centre for Trophoblast Research.
Microbiota drive concomitant expression of IL-17 and the inhibitory receptor PD-1 to regulate effector functions of γδ17 cells in the intestine
Authors: Huang Hsin-I , Hammer Gianna 
Published: January 2023

Abstract
While developmental programming of innate-like γδT cells generates dedicated IFN-γ-producing (γδIFN-γ) or IL-17-producing (γδ17) subsets, emerging evidence suggests these are further shaped by environmental cues. Such cues include the intestinal microbiota, although the nature of microbiota-dependent regulation is poorly understood since some reports hold that microbiota exert strictly activating signals, while other reports show microbiota are strictly suppressive. Whether the impact of microbiota on γδT cells is indeed exclusively binary, and whether regulatory modules stemming from the microbiota can be dynamic in response to changing physiologic conditions remains unknown. Here we identify a microbiota-dependent regulatory module for γδ17 cells in which microbiota concomitantly upregulate IL-17-production and the inhibitory receptor programmed cell death protein 1 (PD-1). Concomitant expression of these two modules, the requirements for microbiota, and preferential upregulation of a PD-1high phenotype is conserved for γδ17 cells resident within multiple mucosal barriers. Importantly, microbiota-driven PD-1 inhibits IL-17 production by endogenous γδ17 effectors. We further show that these two microbiota-dependent modules are dynamic, wherein both PD-1 and IL-17 producing functions are downregulated upon depletion of microbiota, and concomitantly upregulated in response to intestinal inflammation. We also identify enhanced capacity for lipid uptake as an inflammation-associated metabolic response specific to the γδ17 subset, thus linking augmented γδ17 effector functions to dynamic subset-specific metabolic remodeling within the intestine.
Supported by NIH R01-AI088100 awarded to MLS
Multi-transgene AAV immunotherapy re-establishes immune tolerance and provides comprehensive protection in animal model of MS
Authors: Sagadevan Addelynn Sonia , Keeler Geoffrey D , Gaddie Cristina D , Cote Isabelle , Senior Kevin G , Min Daniel , Hoffman Brad E 
Published: January 2023

Abstract
To re-establish long-term immune tolerance in Multiple Sclerosis (MS), our lab had previously developed a pre-clinical Adeno-associated virus (AAV) gene immunotherapy that is capable of preventing and reversing Myelin Oligodendrocyte Glycoprotein (MOG) induced Experimental Autoimmune Encephalomyelitis (EAE). However, MS is a disease that involves multiple myelin proteins including Proteolipid Protein (PLP). Therefore we expanded the capability of our gene immunotherapy to restore tolerance and ameliorate disease to multiple major myelin proteins, simultaneously. In this report we demonstrate that a mixture of 2 individual vectors, AAV MOG & AAV.PLP, was capable of preventing, and more importantly reversing, preexisting EAE disease induced with a mixture of MOG35–55 & PLP139–151 peptides in (C57BL/6JxSJL)F1 mice. To minimize the total vector load we further developed this immunotherapy into a novel single AAV-dual transgene expressing vector (AAV.MOG.PLP) using specific gene linkers for independent expression. Following a single peripheral injection, western blot analysis confirmed stable and simultaneous hepatic expression of both neuroprotein transgenes. When injected into mice 2 weeks before induction of EAE with either MOG35–55 or PLP139–151, or combination of both, the dual transgene AAV immunotherapy significantly reduced or prevented disease in mice compared to controls. Overall, these results demonstrate proof of concept that a single AAV vector simultaneously expressing more than one transgene may be an effective therapeutic treatment for restoring tolerance in an autoimmune disease like MS.
Supported by NIHSarepta Pharmaceuticals NIH R01Act AI128074Project
Gut bacteria-derived isoflavone metabolites ameliorate experimental autoimmune encephalomyelitis (EAE) through estrogen receptor engagement
Authors: Peterson Stephanie R , Jensen Samantha , Dencklau Dalton , Mangalam Ashutosh K 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system which may be influenced by gut bacteria-produced metabolites. We have shown that isoflavone-metabolizing bacteria are less abundant in MS patients as compared to healthy individuals and loss of these bacteria leads to increased disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Isoflavone metabolites can modulate the immune response through binding to estrogen receptors α and β (ERα and ERβ). Thus, we aim to investigate the role of ERα and ERβ in isoflavone-mediated disease protection in EAE by determining ER expression on immune and intestinal epithelial cells as well as receptor specificity for isoflavone-mediated protection in EAE. We hypothesize that isoflavone metabolites induce an anti-inflammatory state via engagement of ERs and that reduction/absence of these molecules may predispose patients to MS development and/or severity. To test this, we administered an isoflavone-containing diet to mice and induced EAE. Mice fed an isoflavone-containing diet developed milder disease than mice fed an isoflavone-free diet while also exhibiting higher expression of ERα, but not ERβ, in the gut. Surprisingly, there was no change in ERβ expression in splenic CD4+ or CD8+ T-cells of mice fed an isoflavone-free versus an isoflavone-containing diet. Mice administered equol also exhibited milder disease than controls. Ongoing experiments using chemical or genetic inhibition of ERα and ERβ signaling will determine the role of these receptors in EAE disease amelioration. Our results suggest that bacterial metabolism of isoflavones leads to EAE disease suppression through utilization of estrogen receptors.
Supported by grants from NIH (T32AI007485, 1R01AI137075-01) and a generous gift from Margaret Heppelmann and Michael Wacek.
Characterization of ARTS-011, a potent and selective TYK2 inhibitor for the treatment of inflammatory disease
Authors: Liang Jiaqi , Liu Yiting , Zhang Xiaobin , Zhang Tao , Liu Xipan , Fu Jia , Cheng Dai , Xiong Wen , Ding Peter , Zhu Cong , Li Fang , Chen Yaoyu 
Published: January 2023

Abstract
The JAK family kinase TYK2 is a key regulator of IL-12 and IL-23 signaling pathways, which have been shown to be involved in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, lupus and inflammatory bowel diseases (IBD). TYK2 inhibition is an attractive therapeutic strategy for human autoimmune diseases. Here, we report a potent oral TYK2 allosteric inhibitor ARTS-011, with high selectivity and potency through optimized binding to the JH2 regulatory domain of the TYK2 protein. ARTS-011 potently binds to TYK2 JH2 domain in binding assay and inhibits IL-23 and IFNα/β induced reporter activation depending on TYK2 kinase. ARTS-011 also inhibits IFNα triggered pSTAT5 potently in human whole blood assay. In addition, ARTS-011 excellent selectivity against other JAK family kinases and panels of receptors, transporters, ion channels, CYP enzymes and the hERG channel. Furthermore, ARTS-011 was also investigated in multiple animal models including IL12/18-induced serum IFNγ mouse model, IL-23-induced mouse psoriasis model and CD40 antibody-induced mouse inflammatory bowel disease (IBD) model. In vivo pharmacodynamic study indicates that ARTS-011 significantly reverses IL12/18-induced IFNγ production in mouse. ARTS-011 also significantly reduces the ear swelling in a dose-dependent manner in IL-23-induced mouse psoriasis model. Lastly, ARTS-011 was highly efficacious in anti-CD40 antibody induced mouse IBD model. In summary, ARTS-011 is a highly selective, potent and orally available small molecule TYK2 inhibitor with suitable pharmaceutical properties as potential therapeutics in inflammatory disorders.
Hv1 proton channels control myeloid landscape and promote glioma progression
Authors: Zheng Jiaying , Wang Lingxiao , Ayasoufi Katayoun , Goddery Emma , Zhao Shunyi , Fain Cori , Johnson Aaron J , Wu Long-Jun 
Published: January 2023

Abstract
Myeloid cells comprising up to 50% of total tumor mass in glioblastoma (GBM) contribute to tumor progression and immunosuppression. Restraining glioma-induced myeloid cell infiltration increases functional T cells within the tumors, improves the efficacy of checkpoint blockade, and significantly extends mouse survival. Here, we focus on an ion channel, voltage-gated proton channel Hv1, which is mainly expressed in myeloid cells and shapes the physiological functions of myeloid cells. Our bioinformatics analysis demonstrated that elevated Hv1 expression in the tumor mass correlates with poor disease prognosis in patients. Using the leading immunocompetent model of GBM in mice, we showed that Hv1 knockout mice (Hv1−/−) exhibit slower glioma progression and prolonged survival. Using in vivo two-photon imaging, we found that myeloid cells infiltrate into tumor mass since early time points and have intimate interaction with tumor cells. Notably, by full-spectrum flow cytometry, we found that Hv1−/− mice have reduced monocyte/macrophage infiltration, and increased PD-1+ CD4+ T cells in the tumor-burdened hemisphere. As a result, we combined anti-PD-1 treatment with Hv1 knockout in the middle stage of glioma, and found that approximately 30% of Hv1−/− mice were cured. Together, our results demonstrated that Hv1 controls myeloid infiltration and could be a novel therapeutic target for the treatment of GBM.
Supported by R01NS110825, R01NS088627
Identifying Antigen Presenting Cells Responsible for Heat Shock Protein-Mediated Cancer Immunosurveillance
Authors: Nayak Devanshi A , Binder Robert J 
Published: January 2023

Abstract
The immune system detects and eliminates nascent, emerging tumor cells. This is mediated primarily by T cells and NK cells. However, the mechanisms that allow efficient T cell priming during cancer immunosurveillance, which is characterized by limited antigen availability, remain unclear. Immunogenic heat shock proteins (HSPs) such as gp96 chaperones minute levels of antigens, in the form of peptides, and allows these to be efficiently cross-presented by APCs, a process that involves the HSP receptor, CD91. Further, engagement of CD91 by HSPs initiates signals for co-stimulation and cytokine production which are necessary for priming anti-tumor responses. We previously showed that mice deficient in CD91 expression in APCs (CD91fl/fl CD11cCre) are more susceptible to chemically induced tumors compared to wildtype littermates. Tumors that emerge in these mice prime poorer T cell responses and are less infiltrated than tumors in wildtype mice. The CD91+ APC subset(s) that are responsible for HSP-mediated T cell priming have not been elucidated. This study seeks to define the APC subset(s) necessary for CD91-mediated immune responses in the tumor microenvironment and tumor-draining lymph nodes. Using genetically tagged HSPs, we track the dispersal of tumor-derived HSPs throughout the myeloid system. We show that HSPs are taken up by multiple DC and macrophage subsets. We identify APC subsets that are responsible for HSP-mediated priming of anti-tumor T cell responses, by adoptive transfer of APCs that acquire tumor-derived HSPs. These studies provide an underlying mechanism of how the immune responses to nascent tumors are initiated. They will also have significant implications for cancer prognosis and therapy.
Supported by NIH (R01 CA233803)
Mechanisms of CD40-dependent cDC1 licensing beyond co-stimulation
Authors: Wu Renee , Ohara Ray A , Jo Suin , Murphy Theresa , Murphy Kenneth M 
Published: January 2023

Abstract
CD40 signaling in conventional type 1 dendritic cells (cDC1s) is required for CD8 T cell-mediated tumor rejection, but the underlying mechanisms are incompletely understood. Here, we identified CD40-induced genes in cDC1 and examined their contributions to anti-tumor immunity. cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T-cell expansion. Loss of 4-1BB, alone or in Cd27−/− mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased apoptosis in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation, which were reversed by re-expression of Bcl-xL. Thus, CD40 signaling in cDC1 not only induces co-stimulatory ligands for CD8 T cells, but also induces Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses.
This work was supported by grants from the NIH (R01AI150297, R01CA248919, and R21AI164142 to K.M.M., and F30CA247262 to R.W.).
Glioblastoma multiforme expresses cell surface PCNA, a potential target for NK cell-mediated immunotherapy.
Authors: Cooksey Luke C , Mathew Porunelloor A 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and carries a dreadful five-year survival rate of 9%. Current treatment options include surgery, chemotherapy, and radiation. Recently, there has been a move to pursue immunotherapy options to improve patient outcomes. These therapies often depend on the identification of molecular markers that are distinctive to the tumor cells. Some markers, such as HER2/Neu and EGFR, are overexpressed on a significant percentage of GBM tumors and are used as targets for immunotherapies. However, to address GBM tumors that do not overexpress HER2/Neu and EGFR, our lab set out to identify novel markers on GBM as future candidates for Natural Killer (NK) cell-mediated immunotherapy. Previously, our lab demonstrated that Lectin-like Transcript-1 (LLT1), membrane-bound Proliferating Cell Nuclear Antigen (PCNA), NKp44 Ligand (NKp44L) and CS1 (CD319) are targets of NK cell-mediated killing of various cancers. Based on these prior studies, we examined their expression on the well-known GBM cell lines LN-229 and LN-18 by flow cytometry using PE-labeled antibodies specific for each marker. PCNA was the lone marker identified to be highly expressed on both LN-229 and LN-18 cells. Based on our results, we concluded that cell surface PCNA is an ideal candidate for NK cell-mediated immunotherapy for GBM. Currently, we are evaluating blocking inhibitory signals to NK cells from the PCNA-NKp44 interaction to target GBM for NK-mediated killing. Recent findings demonstrating the ability to transiently open the blood-brain barrier further increase the feasibility of targeting GBM by NK cells in the future.
Supported by funding from the Osteopathic Scholars in Cancer Research Program grant from the Cancer Prevention and Research Institute of Texas (RP170301) and UNTHSC Intramural grants.