bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Opsonins as sugar sprinkles and B cells as music DJs?”. Effective examples of analogies used as a pedagogical tool in immunology education.
Authors: Ghittoni Raffaella 
Published: November 2024

Abstract
Understanding complex biological processes at the molecular level is a significant challenge for the general public with potential huge societal benefit. It also represents a crucial struggle for undergraduate students approaching immunology for the first time.
Associating complex concepts with more familiar ones, known as analogy, has been shown by several studies to be a valid educational tool used to simplify and visualize complex immunological concepts. Here, I present two effective examples of analogies, used to explain the specific immunological processes of “opsonization” and “somatic hypermutation and affinity maturation”. I will show that the introduction of analogies, following the theoretical explanation of those processes, avoids misconception and contributes in boosting student engagement, thus improving understanding and promoting the storage in permanent memory of the concepts discussed in class. Finally, I will elucidate that the use of multimedia (e.g., video and audio) to present familiar similarities stimulates students’ creativity and prompts them to think about additional examples, which likely helps yield a deeper understanding and better retention of the presented process.
Conditional MHC class I deletion in Tmem119+ microglia attenuates the brain infiltrating virus antigen specific CD8 T cell response.
Authors: Seady Marina , Maynes Mark , Hassani Asma , Thelwell Javonte , Owens Carley , Hansen Michael , Jin Fang , Johnson Aaron 
Published: November 2024

Abstract
Microglia activation is a hallmark feature of the immune response associated with neurological disease. In neuropathological conditions, microglia become fully competent antigen presenting cells and are proposed to perpetuate T cell activation in the brain. Historically, it has been difficult to define the extent microglia enhance CD8 T cell responses in the brain through MHC class I restricted antigen presentation. Using a novel single MHC Class I Cre Lox approach developed by our laboratory in which H-2Kb can be deactivated in Tmem119+ cells, we were able to determine the role of microglial MHC class I following intracranial (i.c.) administration of Theiler’s murine encephalomyelitis virus (TMEV) encoding the model antigen OVA. After confirming the successful deletion of H-2Kb in Tmem119+ cells using spectral flow cytometry, we investigated antigen-specific CD8 T cell expansion and the response of other immune cells in the brain and blood at 7 days post i.c. TMEV-OVA infection. We observed a marked reduction in Kb:OVA epitope specific CD8 T cells in the brain in Tmem119-cre Kb cKO mice compared to Cre- controls. This reduction in in Kb:OVA epitope specific CD8 T cells was not observed outside the CNS. Our results support a role for microglia MHC class I restricted antigen presentation for complete T cell expansion in the brain, implicating this process in protective and pathogenic neurologic conditions.
Isotype-Specific Autoantibody Signatures in Cancer and Sepsis Samples through Multiplex Profiling
Authors: Gilliam Brooke , Pfeifer Justin , McDonald John , Victorino Francisco , Qiang Xiao , Hoberg James , Lie Wen-Rong 
Published: November 2024

Abstract
Many diseases can be characterized by specific autoantibodies. The Luminex™ multi-analyte profiling platform enables simultaneous detection a panel of autoantibodies in a single assay with minimal sample volume. MILLIPLEX™ multiplex assays include the 15-plex Human Cancer Autoantibody Panel, 23-plex Human Cytokine Autoantibody Panel, and 20-plex Human Autoimmune Autoantibody Panel, allowing qualitative profiling of autoantibodies in serum and plasma samples. In this study, we focused on detecting cancer-associated autoantibodies and anti-cytokine autoantibodies in breast cancer, colorectal cancer, sepsis, and healthy control samples (n ≥ 20 in each group). We used the Luminex™ 200™ system and the xMAP™ INTELLIFLEX DRSE instrument for analysis. Preliminary data revealed anti-cytokine IgG autoantibodies against multiple cytokines (e.g., IL-2, IL-4, IFNγ) in cancer, sepsis, and healthy individuals. Additionally, certain cytokine autoantibodies (e.g., IL-1α, IL-12p40, IL-6) were detected in the tested disease samples but not in healthy controls. Isotype profiling demonstrated increased detection of cancer-associated autoantibodies by combining IgG and IgM signatures in cancer samples (e.g., p53, CCNB1/Cyclin B1, SOX2, CTAG1B/NY-ESO-1, Her2/ErbB2). We believe this robust MILLIPLEX™ autoantibody detection and comprehensive isotype profiling can guide further research on autoantibodies as translational biomarkers in a clinical setting.
Transient Therapeutic Inhibition of Multiple Costimulatory Molecules Modulates Persistence of Lung Tissue-resident Memory T cells
Authors: Sethi Gurupreet , Logandha Ramamoorthy Premlal Ashmitaa , Croft Michael 
Published: November 2024

Abstract
Costimulatory molecules, crucial for priming of T cells, development of T cell memory, and establishment of inflammatory diseases, have an unknown role in prolonged survival of Tissue-resident memory T (Trm) cells and the maintenance of relapsing inflammation. Single-cell RNA-seq data from asthmatic lungs revealed high expression of OX40, CD30L, and ICOS on CD4 T cells, aligning with transcriptomic analysis of allergen-reactive mouse CD4 Trm cells in a relapsing asthma model. Accordingly, the transient blockade of ICOSL alone or CD30L and OX40L together during tertiary allergen inhalation effectively reduced the expansion of CD44hiCD62LloCD4+ lung Trm by 40-50%, further reducing to 80-90% when concurrently targeting all three molecules and corresponding to dramatically decreased lung inflammation. Administering FTY720 with the blocking antibodies highlighted costimulatory molecules govern reactivation of both lung Trm and circulatory memory T cells that contribute to the maintenance of Trm pool. Costimulation blockade limited Trm proliferation and their continued responsiveness upon future allergen insults, explaining improved lung function. Dual blockade of ICOSL with OX40L, or ICOSL with CD30L, reproduced the effects of blocking all molecules together in limiting persistence of high numbers of functional Trm, suggesting that targeting ICOS signaling along with CD30 or OX40 signaling holds promise as a clinical treatment for various immune-mediated inflammatory diseases
Neurogenic vasoactive intestinal peptide alters tcr proximal signaling in naive t cells
Authors: Adebamowo Adedola , Rosenberg Kenneth , Singh Nevil 
Published: November 2024

Abstract
Communication between the nervous and immune systems is critical for regulating the immune response. Neuropeptides have been observed to exert modulatory effects on many different lymphocyte subsets. In mouse models, we found peripheral T cells expressed a set of 26 neurotransmitter receptors and exhibited distinct patterns across T cell subsets. The Vasoactive Intestinal Peptide receptor (VIPR1) had an intriguing pattern with high expression in naïve peripheral CD4 T cells and none in Tregs. Upon T cell receptor (TCR) stimulation, VIPR1 expression rapidly declines, suggesting endogenous VIP primarily affects resting naïve T cells. Functionally, treatment with VIP dampened the early activation of naïve T cells, as measured by reductions in proliferative responses and IL-2 secretion in response to antigenic stimulation. Mechanistically, VIP-exposure directly affected signaling via the TCR. Although the early events in the signaling cascade, such as the phosphorylation of ZAP70 was intact, downstream activation of ERK was reduced. Endogenous VIP has a very short lifespan and therefore localized production is likely to impact naïve T cell activation. To map the cellular sources of VIP we generated strains of VIP-lineage-tracing mice. Preliminary analysis shows strong expression in multiple neurons. These data suggest that VIP secreted by neurons has the potential to influence T cell response in a fairly broad manner at the early stage of an immune response.
Formyl Peptide Receptor 1 regulates early control of Mycobacterium tuberculosis infection.
Authors: Nafiz Tanvir Noor , Saqib Mohd , Sankar Poornima , Mishra Bibhuti 
Published: November 2024

Abstract
Formyl peptide receptors (FPR) are playing a pivotal role in phagocyte migration in response to bacterial and host-derived chemoattractants. Despite their established roles, their involvement in immunity to tuberculosis remains unexplored.
In this study, we investigated the contributions of Fpr1 and Fpr2 to host defense against Mycobacterium tuberculosis (Mtb) infection. Fpr1 and Fpr2 expression increased in the lungs of rabbits as early as 3 hours and remained elevated during the chronic phase of infection. Additionally, these receptors were increasingly expressed in neutrophils of mice highly susceptible to infection, implying a potential role in the host response to Mtb.
We assessed bacterial burden, lung damage, and cellular inflammation following infection of Fpr1-/- and Fpr2-/- mice with a hypervirulent W-Beijing lineage strain of Mtb. While Fpr2 deletion exhibited no discernible impact on host resistance, Fpr1 deficiency compromised bacterial control in the lungs. This effect was particularly pronounced in genetically susceptible mice treated with Fpr1-specific inhibitors. In vitro experiments demonstrated that bone marrow–derived neutrophils and macrophages lacking Fpr1 were incapable of controlling intracellular Mtb growth.
Collectively, our findings underscore the differential roles of Fpr1 and Fpr2 in the host defense against Mtb infection, highlighting Fpr1 as a potential therapeutic target for enhancing immune responses against tuberculosis.
FIP200 promotes Mycobacterium tuberculosis pathogenesis independent of its role in autophagy
Authors: Dubey Neha , Woodson Reilly , Kinsella Rachel , McNehlan Michael , Naik Sumanta , Kreamalmeyer Darren , Stallings Christina 
Published: November 2024

Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a critical health issue. Xenophagy, the targeting of Mtb to autophagosomes within infected cells is ineffective at controlling Mtb replication in vivo. We discovered that autophagy-associated proteins function outside of xenophagy to impact Mtb pathogenesis. We reveal a distinct autophagy-independent function of FIP200 in CD11c+ alveolar macrophages (AMs) to control Mtb burden in mice lungs at 7 days post-infection. Intra-tracheal airway labelling shows that despite the abundance of inflammatory cells, including AMs, in airway and interstitium, airway resident AMs precisely exhibit better infection control in Fip200fl/fl-LysM-Cre mice lungs.FIP200, beyond its role in autophagy, is shown to regulate signaling pathways to suppress TNF-induced apoptosis and promote cell survival. Compared to flox control, loss of Fip200 resulted in significantly higher apoptosis in AMs, in the lungs of naïve mice, which is sustained during infection. We also observed higher reactive oxygen species production by the AMs in lungs. This observation extends to Streptococcus pneumoniae infection, where loss of FIP200 in CD11c+ AMs caused similar increase in apoptosis and ROS,with reduced bacterial burden in mouse lungs. Thus, we propose a model where the FIP200 inhibits the apoptosis and ROS production in AMs, which impairs the antimicrobial defense in these cells, thus promoting Mtb infection in the airways following infection.
Modification of Staphylococcal aureus quorum sensing and virulence factor expression by cold plasma treatment
Authors: Melvage Autumn , Smith Carly , Connelly Amanda , Baldomero Genevieve , Lucas Abby , Watkins Amanda , Hickok Noreen , Freeman Theresa 
Published: November 2024

Abstract
Staphylococcal aureus (S. aureus) resides in biofilms and produces virulence factors. Cold atmospheric plasma treatment can be used to kill and reduce bacteria virulence expression. This study will observe the effects of cold plasma treatment on S. aureus killing, biofilm disruption, virulence factor, and quorum sensing gene expression in vitro and in vivo.
S. aureus biofilms were grown in vitro on discs and then treated with plasma (J-Plasma; Apyx Medical Inc.) CFU counts, Crystal Violet Staining, and SEM were conducted to determine biofilm disruption and killing. Gene expression was determined by qPCR for Superoxide dismutase (SodA), Panton-Valentine Leukocidin (luk-PV), alpha-hemolysin (Hla), and AgrB and SarA. A similar study was performed on muscles infected in a rat model, treated and untreated, at Days 0, 4 and 14.
Cold plasma-treated biofilms on discs had significantly less bacterial CFU counts, lower crystal violet absorbance, and visible disturbances of biofilm. qPCR showed a significant reduction of virulence factor and quorum signaling genes. In vivo, all day 4 and 14 muscle samples had significantly higher CFU counts than 6-hour samples. Results showed a fold change reduction after plasma treatment in virulence and quorum sensing gene expression.
Cold plasma treatment disrupts S. aureus biofilm formation and gene expression, both in vivo and in vitro, highlighting the potential of cold plasma treatment to aid in the clearance of S. aureus infections.
Generation of iPSC derived CD19 CAR iNK cells for treatment of autoimmune disorders
Authors: Walsh Ariane , Grandolfo Davide , Pichery Mélanie , Turfkruyer-Housson Mathilde , Richter Mandy , Hublitz Philip , Esquerré Michael , Bombarde Oriane , Holtzinger Audrey , Scheel Andreas , Wagner Nadja , Cernecka Hana 
Published: November 2024

Abstract
Treatment of autoimmune diseases (ADs) relies on broad immunosuppressive agents that are often not curative. Autologous CAR T cell approaches demonstrated disease remission in patients with Systemic lupus erythematosus (SLE). Among cellular abnormalities typical for ADs, NK cells dysfunction was reported. We believe that using iPSC derived CD19 CAR NK cells (iNK cells) to eliminate disease-causing circulating plasma cells could be a novel therapeutic approach for ADs mediated by B cells. Evotec’s validated GMP iPSC line was genetically modified by a knock-in of a CD19-CAR and differentiated into iNK cells using a feeder-free 3D differentiation process. Successful knock-in was confirmed by flow cytometry. Expression of the CAR did not negatively impact the differentiation of the iNK cells. The CD19 CAR iNK cell phenotype and scRNA sequencing profiles are comparable to blood-derived NK cells. To evaluate the ability of CD19 CAR iNK cells to selectively eliminate primary B cells, patient-derived B cell chronic lymphatic leukemia (CLL) cells and primary B cells from healthy donors were co-cultured with CAR iNK cells. Compared to wildtype (WT) iNK cells, CD19 CAR iNK showed specific killing of CD19-positive CLL cells and primary B cells. iPSC-derived CD19-CAR NK cells show increased cytotoxicity and specific targeting of CD19 positive primary patient and healthy subject derived B cells, demonstrating their potential suitability for the treatment of ADs such as SLE.
C57BL/6J-Trex1em3Lutzy/J KO mouse as a type 1 IFN dependent model for SLE preclinical drug discovery
Authors: Case Laure , Presa Max , Tata Saurabh , Martin Paige , Tracey Katelyn , Lutz Cat 
Published: November 2024

Abstract
Systemic Lupus Erythematosus is a chronic autoimmune disease characterized by a broad spectrum of clinical manifestations. An important role of the type I interferon (IFN) pathway has been identified in SLE patients. No one mouse model completely recapitulates the complexity of the human disease. Nonetheless, mouse models of SLE have been instrumental in our understanding of the genetic and cellular requirements for SLE induction and represent a valuable resource for testing SLE therapies and drug candidates in vivo. Here we present preclinical reference data in a Trex1KO mouse model generated at the Jackson Laboratory using CRISPR technology. Trex1KO mice have a median survival of approximately 165 – 185 days. Body weight is significantly reduced in both male and female KO versus WT. Unlike NZBWF1/J and MRL/MpJ mouse models that develop lupus nephritis, the Trex1 KO develops dilated cardiomyopathy due to leukocyte infiltration and cardiomyocyte degeneration. Here we treated KO mice with anti-IFNα antibodies through 32 weeks of age. We observed a significant treatment effect on survival, reduction in leukocyte infiltration and degeneration of the heart, and percentage of T peripheral helper T cells in spleen. A mouse model recapitulating a role for type I IFN in disease pathogenesis has been lacking in the common models of SLE, and these data indicate that the Trex1KO model is relevant for the screening of targeted therapies of type I IFN and related pathways.
Vasoactive Intestinal Polypeptide in the Enteric Neural Plexus Promotes Microbiome Diversity and Resistance to GvHD
Authors: Li Yiwen , Wang Shuhua , Zhang Hanwen , Liu Yutong , Passang Tensin , Giver Cynthia , Waller Edmund 
Published: November 2024

Abstract
Graft-versus-host disease (GvHD) in allo-transplant recipients is characterized by donor T cell- mediated damage to recipient organs and changes in the gut microbiome. Vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, directs T cell responses towards a Th2 phenotype while inhibiting proinflammatory cytokine production. VIP-producing enteric neurons contribute to the mucosal barrier and maintain gut microbiome homeostasis. The impact of VIP production by host cells on GvHD remains unclear. We examined the effect of endogenous VIP synthesis in modulating GvHD in multiple murine allo-BMT models. VIP knock-out mice were exquisitely sensitive to GvHD, experiencing activation and expansion of Th1- and Th17-polarized T cells and early death. Transplanting radiation chimeric mice in which the VIP gene was knocked out in either hematopoietic or non-hematopoietic cells demonstrated that VIP production by non-hematopoietic tissues limited the GvHD activity of donor T cells. Immunofluorescence staining demonstrated VIP expression in enteric neurons in allo-BMT recipients, consistent with local effects of VIP on T cells and the gut microbiome. VIP- KO mice had lower gut pH, higher frequencies of Bacillota species, and less microbiome diversity post-transplantation. These data support the crucial role of VIP in maintaining the diversity of the gut microbiome with beneficial commensal species and in modulating the alloreactivity of donor T cells after allo-BMT.
Entolimod, a clinical stage flagellin derivative, improves clinically relevant chemo-immunotherapy responses in pre-clinical triple negative breast cancer
Authors: Brackett Craig , Aldrich Alyssa , Punch Patrick , Greene Kellee , Molodtsov Ivan , Gudkov Andrei , Abrams Scott 
Published: November 2024

Abstract
Chemotherapy+anti-PD-1 is FDA approved and has improved outcomes for locally advanced and metastatic PD-L1+ triple negative breast cancer (TNBC). Unfortunately, a need still exists to improve this chemo-immunotherapy (CTx-I) platform especially in advanced disease. Entolimod, an agonist of the TLR5 and NAIP5 receptors, is our flagellin derivative which has successfully completed Phase I safety trials. We previously showed that systemically administered entolimod enhances durable antitumor immunity against metastasis of 4T1, a preclinical PD-L1+ TNBC model. However, the antimetastatic activity of single-agent entolimod was not completely effective, highlighting the need to combine entolimod with additional immune-based modalities such as CTx-I to further improve tumor control. Here, we used Paclitaxel+anti-PD-1 as a clinically oriented CTx-I platform in pre-clinical metastatic TNBC models. CTx-I+entolimod effectively controlled primary tumors and reduced lung metastatic burden more so than the single or double agent treatments. Consistent with our prior work that neutrophils express functional TLR5, depletion abrogated CTx-I+entolimod efficacy. Collectively, the immune enhancing effects of entolimod can be leveraged to boost urgently needed CTx-I outcomes in TNBC. Because entolimod has successfully completed Phase I clinical trials, this preclinical work supports the rationale design of a clinical trial that combines CTx-I with entolimod as an effective immunotherapy platform.
Adeno-Associated Virus-Mediated IL-2 Delivery in Liver Cancer: Immune Activation and Therapeutic Challenges
Authors: Chuang Ya-Hui 
Published: November 2024

Abstract
Hepatocellular carcinoma (HCC), a prevalent primary liver cancer, poses a significant global health challenge. The liver's immune population is selectively enriched in natural killer (NK) cells, natural killer T (NKT) cells, and CD8+ T cells, which play critical roles in anti-tumor responses. Interleukin-2 (IL-2) holds promise in activating these immune cells for cancer therapy, but its short half-life and systemic toxicity limit its application. This study aimed to enhance hepatic NK, NKT, and T cells using a liver-preferred adeno-associated virus (AAV) to deliver IL-2 (AAV-IL-2) sustainably for HCC therapy in a syngeneic orthotopic mouse model. At first, we administered high, medium, and low doses of AAV-IL-2 to naive mice, revealing that only the medium dose expanded hepatic NK, NKT, and T cells without inducing toxicity. In HCC-bearing mice, low-dose AAV-IL-2 treatment had minimal effects. Medium-dose AAV-IL-2 treatment expanded and activated hepatic NK, NKT, and T cells but also induced intratumoral CD8+ T cell exhaustion. Notably, medium-dose AAV-IL-2 had no suppression of tumor progression but higher mortality. These results underscore the challenging balance required for effective HCC treatment with IL-2, as a medium dose successfully enhances hepatic immune cells but simultaneously induces CD8+ T cell exhaustion and higher mortality.
Characterization of CISH-knockout NK cells derived from human peripheral blood and evaluated the antitumor effects in allogeneic glioblastoma
Authors: Nakazawa Tsutomu , Morimoto Takayuki , Maeoka Ryosuke , Matsuda Ryosuke , Nishimura Fumihiko , Tsujimura Takahiro , Nakagawa Ichiro 
Published: November 2024

Abstract
Background: Glioblastoma (GBM) is the most common malignant brain tumor. Allogeneic natural killer cells (NKCs) have gained considerable attention as promising immunotherapeutic tools against cancer, where gene-edited NKCs would result in effective anti-cancer treatment. This study focused on the immune checkpoint molecule cytokine-inducible SH2-containing protein (CISH) as a critical negative regulator in NKCs.
Methods: We generated human primary CISH-deleted NKCs (NKC dCISH) by combining our specific NKC expansion method and CRISPR/Cas9. The genome-edited NKCs underwent microarray analysis. The anti-GBM activity of the genome-edited NKCs was evaluated in vitro and further detected in vivo antitumor effects using xenograft brain tumor mice.
Results: We successfully induced NKC dCISH derived from human peripheral blood. Gene set enrichment analysis (GSEA) using microarrays revealed that the enriched genes were involved in effector functions in NKC dCISH. CISH deletion enhanced NKC-mediated apoptosis induction against allogeneic GBM cells and spheroids. Intracranial administration of the allogeneic CISH-deleted NKCs prolonged the overall survival of xenograft brain tumor mice.
Conclusion: CISH deletion enhanced NKCs' effector functions and NKC-mediated antitumor effects in allogeneic GBM. The genome-editing NKCs could be a promising immunotherapeutic alternative for patients with GBM.