bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bhlhe40 in Group 3 Innate Lymphoid Cells Shapes TL1A-dependent Commensal T cell Immunity
Authors: Yang Wei , Pires Silvia , Oguntunmibi Seun , Diehl Gretchen , Edelson Brian , Longman Randy 
Published: November 2024

Abstract
A central feature of intestinal mucosal immune system is the ability enable antigen specific tolerance to the gut bacteria. Genetic variants in TNFSF15 (which encodes protein TL1A) are linked to inflammatory bowel disease and have implicated roles for TL1A in regulating both T cell and innate lymphoid cells (ILC), but how these cellular pathways coordinate a response to limit intestinal inflammation is not completely understood. Deletion of TL1A receptor Tnfrsf25 (also called DR3), we demonstrate that TL1A signaling is required for efficient generation of RORγt+Foxp3+ intestinal iTregs at steady state. To investigate if this response resulted from DR3 deletion in T cells or the potential role for DR3 signaling in ILCs to regulate iTregs indirectly, we generated antigen specific transgenic T cells to H. Hepaticus (Hh) with DR3 deletion. Our results reveal that TL1A signaling is dispensable on T cells but required on ILC3s to regulate the balance between intestinal iTreg and inflammatory Th17 cells. RNA sequencing of ILC3s revealed the induction of Bhlhe40 in response to TL1A stimulation. Using conditional deletion models, we defined Bhlhe40 as a transcriptional regulator of ILC3 expression of Tnfsf4 (OX40L) and the subsequent requirement for ILC3-specific Bhlhe40 and Tnfsf4 in promoting Hh-specific Treg induction. These data reveal a novel function for TL1A and downstream transcription factor Bhlhe40 in enabling ILC3 coordination of gut commensal T cell immunity.
Examining the antitumorigenic effects of Ruminococcus gnavus
Authors: Laughlin Colin , McPherson Alex , Pandey Surya , Shapira Jake , Phelps Catherine , Lee Amanda , Randhawa Simran , Gottschalk Rachel , Yang Zhen , Hinterleitner Reinhard , Meisel Marlies 
Published: November 2024

Abstract
Melanoma is one of the most commonly occurring cancers in the world, with increasing occurrence over the past several decades. Common treatment regimens for melanoma include immune checkpoint inhibitor (ICI) therapy, which enhances interferon-γ production in CD8 T cells (Tc1). Despite showing efficacy in some patients, a majority of melanoma patients are resistant to ICI therapy. Prior studies have demonstrated the ability of the gut microbiota to impact Tc1 antitumor responses and ICI therapy efficacy. In analyzing top gut bacteria enriched in ICI-responders, Ruminococcus gnavus (R. gnavus) is a commonly identified species. Here we demonstrate the tumor restraining properties of R. gnavus in subcutaneous, spontaneous, and metastatic cancer models. Further, gnotobiotic monocolonization experiments demonstrate the ability for this bacterium to restrain tumor growth independent of a complex microbiome. Analyzing the mechanism behind how R. gnavus causes melanoma growth suppression in our model, we have demonstrated requirements of bacterial viability and aryl hydrocarbon receptor (AHR) activation. Colonization with R. gnavus at various tumor timepoints was able to induce a significant Tc1 response locally in the tumor and systemically in lymphoid organs. Finally, we found R. gnavus colonization to facilitate ICI efficacy in our model. This study uncovers a potential mechanism of how a common ICI-response associated bacterium enhances ICI efficacy in melanoma.
Preclinical pharmacology of S-1117, a novel engineered Fc-fused IgG cleaving enzyme, for chronic treatment of autoantibody-mediated diseases
Authors: Sanmarco Liliana , Pellerin Alex , Anderson Jordan , Rollins Nathan , Newton Andita , Green Tobias , Le Nam , Peckner Ryan , Mande Purvi , Xing Xi , Manasson Julia , Higginson-Scott Nathan , Sundy John , Otipoby Kevin , Mascanfroni Ivan 
Published: November 2024

Abstract
Pathogenic autoantibodies are key effectors of inflammation, promoting complement activation and immune cell responses that cause tissue damage in autoantibody-mediated diseases such as myasthenia gravis. IgG-proteases represent a new therapeutic opportunity. Here we present S-1117, a novel Fc-fused pan-IgG protease, engineered using a proprietary machine learning enabled platform to reduce immunogenicity and augment manufacturability and stability while maintaining enzyme activity. S-1117 cleaves soluble IgG and the BCR on memory B cells with comparable potency and significantly reduces antibody-dependent cytotoxicity (ADCC) and immune complex-mediated PBMC activation in vitro. When tested in vivo, a deep reduction of human IgG (&gt;90%) occurred within 30 minutes after dosing. A PK/PD model developed for human projections predicts rapid, deep and sustained reduction of IgG levels. In addition, in an anti-glomerular basement membrane (GBM) model, a prototype Fc-fused pan-IgG protease reduced complement activation, IC deposition, which correlated with reduced proteinuria, blood urea nitrogen and renal pathology. In summary, S-1117 is a novel engineered pan-IgG protease that demonstrates rapid and sustained reduction of IgG levels and reduces multiple pathological manifestations in a murine nephritis model. Given its ability to address multiple pathogenic mechanisms as a single drug, it has the potential to achieve improved clinical outcomes in autoantibody-mediated diseases.
Biochemical and Immunological Characterization of 3HKA; a Novel Anti-inflammatory Biogenic Amine
Authors: Clement Cristina , Buque Aitziber , Mota Ines , Nanaware Padma , Santambrogio Laura 
Published: November 2024

Abstract
Tryptophan (Trp) catabolism generates over fifty metabolites, including kynurenines, powerful mediators of immune regulation. We recently reported that: (i) lymphatic endothelial cells (LEC) and dendritic cells (DCs) secrete a previously unidentified biogenic amine, 3HKA, which derives from a lateral pathway of Trp catabolism (ii) 3HKA exhibits a clear anti-inflammatory profile by inhibiting the STAT1/NF-kB pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines; most notably, IL-6, IL12p70 and TNFa; (iii) in vivo, 3HKA exerts protective effects in the experimental model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring. In a model of nephrotoxic lupus, 3HKA improved proteinuria and serum urea nitrogen, overall ameliorating the immune-mediated glomerulonephritis and renal dysfunction. Additionally, 3HKA and 30 newly generated 3HKA analogs have been proven effective in decreasing ex vivo inflammation in PBMC samples of Lupus patients.
Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice
Authors: Grazda Rachel , Seyfried Allison , MacNamara Katherine 
Published: November 2024

Abstract
Treatments for severe aplastic anemia (SAA) rely on stem cell transplantation and immunosuppressive therapies. Immune-mediated destruction and inflammation drive SAA, but the mechanisms that lead to persistent inflammation are unknown. Using an established mouse model of SAA, we observed increased apoptotic cells within the bone marrow (BM), correlating with impaired efferocytosis. Single-cell transcriptomics revealed heterogeneity among SAA BM monocytes and enhanced inflammatory signatures. Notably, increased expression of Sirpa and Cd47 were observed on monocytes in murine SAA, as well as human SAA patients. The don’t eat me signal CD47 was increased on apoptotic BM cells, concurrent with markedly increased signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced CD47-positive apoptotic cells. Lipidomics revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA mice. Resolvin E1 (RvE1) therapy improved efferocytosis, BM cellularity, platelets, and survival. Our data link impaired efferocytosis with SAA and suggest that failed inflammation resolution contributes to disease progression. We demonstrate that SPMs, such as RvE1, offer novel treatments for SAA that do not rely on immune suppression.
Regulatory T cells as key modulators of breast cancer brain metastasis
Authors: Adam Isam , Longworth Aaron , Lawson Devon 
Published: November 2024

Abstract
Breast cancer brain metastasis (BCBM) is a disease with a dismal prognosis. Current therapeutics often fail due to the distinct immune environment within the brain. Thus, there is a critical need to understand infiltrating immune cells within BCBM. Regulatory T cells (Tregs) are a population of immunosuppressive T cells that have been implicated in the pathogenesis of several tumor types. Their functions are widely explored in these contexts, but an understanding of these functions in the brain is lacking. To elucidate the role of Tregs in BCBM, we intracranially injected E0771 cells into C57BL/6J mice and monitored tumor development and immune infiltration for 14 days. Using Foxp3-DTR mice, we assessed the effects of Treg depletion on tumor burden and the immune microenvironment. We found that Tregs prominently infiltrated BCBM tumors throughout tumor progression. Furthermore, Treg depletion led to a massive accumulation of CD8+ and CD4+ T cells and a near-complete loss of tumor burden. Additionally, we demonstrated that microglia, a population of brain-resident macrophages, displayed a more prominent antigen presentation phenotype in Treg-depleted mice. We hypothesize that BCBM-infiltrating Tregs suppress the infiltration and activation of CD8+ and CD4+ T cells by inhibiting antigen presentation in microglia. The mechanisms by which Tregs exert this function are unclear but can lead to the identification of novel therapeutic targets for the treatment of brain metastases.
Mitigating adverse effects of B cell depletion therapy on acute respiratory virus infections through IFN-β intervention treatment.
Authors: Allushi Bujana , Chlebicz Magdalena , Turner Sean , Kovats Susan , Axtell Robert 
Published: November 2024

Abstract
In autoimmune patients, the use of disease-modifying therapies (DMTs) can compromise immunity to viral infections. The COVID-19 pandemic generated interest in the effects of two DMTs on acute viral infections:B cell depletion therapy (α-CD20) and Interferon-beta (IFN-β) therapy. Severe acute viral infections have been associated with B cell depletion therapy, while IFN-β is believed to provide protection due to its antiviral properties. The goal of our study is to elucidate the individual and combined effects of α-CD20 and IFN-β during acute respiratory viral infections in mice. In our study, B cell depletion was achieved by administering α-CD20 three times every 5 days, starting 7 days before influenza A virus (IAV) infection, while IFN-β was given on days 1 and 2 post-infection. When administered alone, α-CD20 resulted in increased weight loss, reduced viral clearance, heightened lung-infiltrating myeloid cells, and elevated inflammatory cytokines in the blood on day 9 post-infection. T cell responses to IAV were not inhibited by α-CD20. While IFN-β alone did not protect against IAV, co-administration of IFN-β with α-CD20 effectively mitigated adverse effects of B cell depletion, by reducing viral load, mitigating morbidity, and slowing the infiltration of myeloid cells into the lung. These data demonstrate IFN-β’s ability to counteract α-CD20’s negative impact on viral infections, providing insights for potential treatment strategies in autoimmunity during viral outbreaks.
Neuroinflammation in Cryptococcal Post-infectious Inflammatory Response Syndrome (PIIRS) is reduced by Ruxolitinib, a Janus Kinase (JAK) inhibitor.
Authors: Hargarten Jessica , Anjum Seher , Xu Jintao , Ssebambulidde Kenneth , Song Brian , Ganguly Anutosh , Vaughan Malcolm , Scott Terri , Hammoud Dima , Olszewski Michal , Williamson Peter 
Published: November 2024

Abstract
Recently, a PIIRS was described in non-HIV infected cryptococcal meningoencephalitis (CM) as a significant cause of neuropathology and mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull's rigid structure. In the present study, transcriptional profiling of RNA from brains of PIIRS model mice at peak inflammation identified a predominance of STAT1/STAT3-associated downstream genes. Since JAK is known to activate both pathways, we hypothesized that the JAK/STAT inhibitor ruxolitinib could reduce neuro-damaging inflammation from CM. Treatment with ruxolitinib reduced intrathecal STAT1/STAT3-associated gene expression as well as CD44hiCD62loCD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells with improved neuropathology and weight. Based on these data, the first human treatment of PIIRS with ruxolitinib was initiated in 5 patients with residual inflammation despite corticosteroids (CS). Ruxolitinib reduced cerebrospinal fluid (CSF) activated HLA-DR+ CD4+ and CD8+ cells, NK cells, and inflammatory monocytes as well as soluble markers sIL-2R, and IL-10 with a trend in IL-6 on a constant dose of CS. MRI brain imaging also demonstrated significant improvements and therapy was well tolerated. Together, these findings demonstrate a role for the JAK/STAT pathway in PIIRS and support ruxolitinib as a potential adjunctive therapy for further randomized clinical trials of PIIRS as a steroid-sparing therapeutic.
Host guanylate binding proteins participate in parasite control during Leishmania infection
Authors: Fry Lucy , Kelner Noah , Weinkopff Tiffany 
Published: November 2024

Abstract
Cutaneous leishmaniasis (CL) is a debilitating neglected tropical disease causing lesions ranging from self-healing to permanent disfigurations. A predominant Th1 response relying on IFNγ production leads to parasite control during CL. Although IFNγ is mainly responsible for activating macrophages to produce NO leading to parasite control, IFNγ can activate other downstream pathways involved in cell autonomous immunity including the activation of guanylate binding proteins (GBPs), a class of interferon-inducible GTPases. GBPs play a role in host defense against some intracellular pathogens, but minimal work has been done to understand the role of GBPs during Leishmania infection. Utilizing RNA-Seq we found several GBPs are upregulated in lesions during L. major infection in mice. Single-cell RNA-Sequencing revealed macrophages as the main cell type expressing Gbps, including Gbp2, Gbp5, and Gbp7 during infection. Additionally, Gbp expression was not unique to L. major infection; both L. amazonensis and L. mexicana infection in vivo resulted in elevated Gbp expression. Preliminary in vitro experiments show macrophages from GBPChr3 KO mice harbor increased numbers of parasites compared to control macrophages with and without IFNγ treatment. Consistent with in vitro findings, infected GBPChr3 KO mice exhibit increased pathology compared to control mice. Together these data suggest GBPs participate in the defense against Leishmania parasites.
Monocyte-derived macrophages in gut mesentery contribute to the host defense against Salmonella Typhimurium infection.
Authors: Kim Jiseon , Dominguez Joseph R , Kim Seung Hyeon , Chan Carissa , Groisman Eudardo , Kim Ki-Wook 
Published: November 2024

Abstract
Macrophages are essential in clearing microbial pathogens and orchestrating inflammation and resolution of tissues. Recently, two distinct resident macrophage populations (LYVE1hi and LYVE1lo/-) were identified in the mesothelium of serous tissues, including mesentery and peritoneum; however, their pathophysiological functions are poorly understood in inflammatory conditions such as pathogen infection. In the present study, we investigated the heterogeneity and ontogeny of macrophages residing in the mesothelium of gut mesentery, and their function in Salmonella Typhimurium (STm) infection. Fate-mapping approaches using CX3CR1CreER and Ms4a3Cre mice demonstrated that Tim4(+) mesenteric macrophages originate from embryonic precursors and Tim4(-) subsets are replenished from circulating monocytes. The ontogeny of Tim4(-) macrophages was confirmed by CCR2 KO mice. Intragastric infection of STm showed that bacteria first reached the mesenteric lymph node through the gut mesentery and induced immune cell infiltration prior to the dissemination to other tissues. To determine the role of Tim4(-) macrophages, mouse mortality was observed in mice lacking Csf1 in Wt1-expressing stromal cells (WT1Δcsf1 mice) and CCR2 KO. The mouse survival rate was significantly decreased in CCR2 KO or WT1Δcsf1 mice in comparison with their control mice. Our data highlight that monocyte-derived Tim4(-) macrophages might be essential in host defense against enteric bacterial infection.
Establishment of a humanized mouse model for the study of co-infection with Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis
Authors: Bohorquez Jose , John Sahana , Ansari Danish , Florence Jon , Yi Guohua 
Published: November 2024

Abstract
Tuberculosis (TB), caused by Mycobacterium Tuberculosis (Mtb), continues to be one of the most important public health threats worldwide, being the second deadliest infectious disease, after COVID-19. The human immunodeficiency virus (HIV) is another equally important global public health issue. Co-infection with HIV and Mtb has severe effects in the host, with people living with HIV being 15-21 times more likely to develop active TB. The use of an appropriate animal model for HIV/Mtb co-infection that can recapitulate the diversity of the immune response in humans would be a very useful tool for basic and applied research. The present study aimed to develop a humanized mouse model for the study of HIV-Mtb coinfection. Using NSG-SGM3 mice that can engraft human stem cells, our results showed that these mice differentiated a full-lineage of human immune cell subsets. After co-infection with HIV and Mtb, the humanized mice showed decreased CD4+ T cell counts overtime with elevated HIV-1 load in sera, similar to the infection pattern in humans. Additionally, Mtb also caused infections in lungs and spleen, and induced the development of lesions in the lungs, detected by CT scan and histopathology. Distinct metabolomic profiles were observed in the different mice groups after infection. Our results suggest the capacity of this mouse model to recapitulate the effects of HIV and Mtb infections/co-infection, in the human host at a pathogenic, immunologic and metabolic level
RUNX2 transcriptional activity is required for CD26high CD4+ T cell development
Authors: Ruffin Ayana , Ware Micheal , Wyatt Megan , Cole Anna , Wittling Megen , Rangel Rivera Guillermo , Lesinski Gregory , Paulos Chrystal 
Published: November 2024

Abstract
Adoptive T cell therapy (ACT) is rapidly growing as a promising treatment option for patients who relapse or fail to respond to immunotherapy. However, in the treatment of solid tumors with ACT, many therapies fail to maintain long-term durability. We posit that CD4+ T cells expressing high levels of CD26 (CD26high T cells) would be a potent ACT product. We previously reported that they express an array of chemokine receptors, dynamic cytokine profile and regressed tumors better than other T helper subsets. Here, we developed novel cytokine priming strategies to enrich CD26high T cells from the blood of healthy donors and cancer patients. We identified a unique suite of transcription factors, including RUNX2, that are elevated on CD26high T cells. We also discovered that CD26high T cells overexpress a distinct patterns of cytokine receptor including IL-2Ra, IL-7R, IL-18R and IL-12Rβ1. Targeting these receptors via recombinant cytokine priming strategies resulted in three-to-five-fold expansion of CD26high T cells from bulk or Naive CD4+ T cells. Inhibiting RUNX2 DNA binding via small molecule inhibitors CADD522 and DIPQUO resulted significant reduction in development of CD26high CD4 T cells and decreased their cytokine production. These data suggest that RUNX2 may regulate the development and function of CD26high CD4 T cells. Taken together, these results provide evidence for the use of CD26high CD4 T cells in the treatment of solid malignancies with ACT.
Engineered IL2 for improved treatment of bladder cancer
Authors: Liao Yiji 
Published: November 2024

Abstract
Bladder cancer (BC) remains a formidable challenge despite its immunogenic nature and responsiveness to FDA-approved immunotherapy. Interleukin-2 (IL2), a potent cytokine with potential for cancer treatment, faces obstacles such as the simultaneous activation of immunosuppressive regulatory T cells (Tregs), high toxicity, and a short half-life. CD122-directed IL2 therapy (IL2c) has shown success in mouse BC models. To address clinical challenges, we engineered two IL2/anti-IL2 antibody (F10) fusion proteins: F10 IC (native IL2), potentially biased toward effector cell activation, and F10 H9T (H9T, an engineered IL2), potentially favoring memory T cells.
In vitro F10 H9T induced stem-like T cells (TCF-1+) and central memory T cells (CD44+CD62L+), while IL2c promoted Teff cell (CD44+CD62L-) differentiation. In vivo, using an orthotopic mouse bladder cancer model (n=10/group), F10 IC was superior in activating anti-tumor Teff and NK cells over F10 H9T and IL2c. Unexpectedly, F10 IC also induced TCF-1+ T cells, suggesting a potentially valuable dual effect, but further validation is required.
We provide a roadmap for designing and translating immunomodulatory cytokine/antibody fusion proteins to overcome challenges associated with IL2-based cancer therapies.
IL-33 downregulates human IL-33 expression in the pulmonary vasculature during allergic airway inflammation
Authors: Hollinger Maile , Howard Chanie , Decker Donna , Blaine Kelly , Hrusch Cara , Grayson Emily , Aneas Ivy , Camacho Daniel , Schoettler Nathan , Ober Carole , Nobrega Marcelo , Sperling Anne 
Published: November 2024

Abstract
IL-33 is abundantly expressed in the human lung, where it is involved in pathogen defense, barrier homeostasis, and development of type 2 allergic responses. We recently identified a 5 kb region within a GWAS-defined segment that acts as an enhancer barrier element in vivo and in vitro. We showed that the asthma-associated SNP rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein in human plasma. To study this human regulatory region in vivo, we engineered a novel IL33 reporter mouse containing the human 5kb regulatory element to reflect human IL33 expression. As expected, human and mouse IL33 reporters were primarily expressed in non-overlapping cell types: human IL33 reporter was mostly expressed in vascular and lymphatic endothelium, while mouse IL33 reporter was expressed in ATII epithelium. Interestingly, we demonstrate negative regulation of human IL33 in lung endothelium during house dust mite (HDM)-induced allergic airway inflammation, which was dependent on the human 5kb regulatory region. Similar downregulation of endothelium IL-33 was induced with only IL-33 treatment in vivo and in vitro. We found that this IL-33-induced negative feedback loop worked through the induction of cytoplasmic IL33 mRNA instability. Together, these data reveal the importance of the asthma-associated human 5kb enhancer element in regulating human IL33 expression in a cell type- and context-dependent manner.