bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a gp96-Ig vaccine for COVID-19
Authors: Strbo Natasa , Fisher Eva , Padula Laura , O’Neill Katelyn Elizabeth 
Published: February 2023

Abstract
The rapid spread of the global COVID-19 pandemic has put pressure on the development of a SARS-CoV-2 vaccine to address global health concerns. We generated a gp96-Ig-secreting vaccine expressing full-length spike or “S” glycoprotein of SARS-CoV-2 via a cell-delivered platform. Vaccine is based on the secreted heat shock protein, gp96-Ig, vaccine strategies that induces an antigen specific CD8+ cytotoxic T lymphocytes (CTLs). Secreted heat shock proteins were successfully used to induce immunogenicity against tumors, HIV/SIV, ZIKA, malaria in different animal models. Importantly, this vaccine strategy has proven to be effective in delaying virus acquisition as well as improving survival of non-small cell lung cancer patients in clinical trials. The principle of this vaccine relies on a cell-based, secreted gp96-Ig chaperoning antigenic proteins that are efficiently taken up and cross presented by activated dendritic cells (DC) to CD8 cytotoxic T lymphocytes (CTL), thereby stimulating an avid, pathogen-specific, cytotoxic CD8+ T cell response. We showed that our vaccine platform effectively stimulates a robust cellular immune response against protein S. Moreover, we confirmed that gp96-Ig, secreted from allogeneic cells expressing full-length protein S, generates powerful, protein S polyepitope-specific CD4+ and CD8+ T cell responses in both lung interstitium and airways. These findings were further strengthened by the observation that protein-S-specific CD8+ T cells were induced in human leukocyte antigen (HLA)-A2-02-01 transgenic mice thus providing encouraging translational data that the vaccine is likely to work in humans, in the context of SARS-CoV-2 antigen presentation.
Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein
Authors: Suryadevara Naveen Chandra , Shrihari Swathi , Gilchuk Pavlo , VanBlargan Laura A. , Binshtein Elad , Zost Seth J. , Nargi Rachel S. , Sutton Rachel E. , Winkler Emma S. , Chen Elaine C. , Fouch Mallorie E. , Davidson Edgar , Doranz Benjamin J. , Carnahan Robert H. , Thackray Larissa B. , Diamond Michael S , Crowe James E. 
Published: February 2023

Abstract
Most human monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 isolated to date recognize the spike (S) protein receptor-binding domain (RBD) and block virus interaction with the cellular receptor angiotensin converting enzyme 2 (ACE2). We isolated a panel of human mAbs binding to diverse epitopes on the spike protein N-terminal domain (NTD) from SARS-CoV2 convalescent donors and found that a minority of these possessed neutralizing activity. Two mAbs (designated COV2-2489 and COV2-2676) inhibited infection of both authentic SARS-CoV-2 and recombinant chimeric VSV/SARS-CoV-2 reporter viruses. We mapped their binding epitopes by alanine scanning mutagenesis and selection of functional SARS-CoV-2 S protein variants with mutations in the NTD that conferred resistance to recombinant chimeric VSV/SARS-CoV-2 reporter virus. Mechanistic studies showed that the antibodies neutralize in part by inhibiting at a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 prevented infection and disease in mice when administered either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, a subset of human NTD-specific mAbs protects against infection using multiple functional attributes including neutralizing activity and Fc-mediated activities.
Role of aging-associated Treg cell accumulation in experimental autoimmune encephalomyelitis (EAE) — a model of late-onset multiple sclerosis (MS)
Authors: Wang Weikan , Oh Jiyoung , Thomas Rachel , Su Dongming 
Published: February 2023

Abstract
MS, a T cell-mediated autoimmune demyelinating disease of the central nervous system (CNS), has not been sufficiently studied in the elderly, despite instances of late-onset MS. Regulatory T (Treg) cells play an ameliorative role in MS disease onset and severity. Given that the aged immune system exhibits relatively enhanced thymic Treg cell generation and accumulated peripheral Treg cells, the role of Treg cell in aged MS patients remains to be elucidated. Using the mouse model EAE, we found that the aged mouse late-onset EAE occurs with two disease types. In Type I, EAE onset was delayed in the age mice, but the disease became more severe once onset. Alternatively, in Type II, some aged mice never developed severe symptoms than young mice until a second antigen challenge was given, which led to more a progressive disease course than their young counterparts. These features were potentially associated with a disparate distribution of Treg cells in the aged peripheral lymphoid tissues and CNS during the disease. The aged EAE mice had a higher proportion of polyclonal Treg cells in the peripheral lymphoid tissues, but a lower proportion of Treg cells specific for myelin oligodendrocyte glycoprotein (MOG) in the CNS, compared to young counterparts. Transient inhibition of accumulated polyclonal Treg cells in the periphery partially ameliorated disease severity in the aged mice, which was accompanied by increased MOG-specific Treg cells in the CNS. Therefore, we suggest that accumulated polyclonal Treg cells in the aged periphery are detrimental for CNS repair processes during neuronal inflammation in aged MS mice, potentially due to hampering trafficking of MOG-specific Treg cells into the CNS.
Dual IgA/IgG family plasmablast-derived mAbs from peripheral blood of individuals at risk for rheumatoid arthritis are polyreactive to autoantigens and intestinal bacteria
Authors: Chriswell Meagan , Bloom Michelle , Seifert Jennifer A , Feser Marie , Demoruelle M. Kristen , Deane Kevin D. , Norris Jill M. , Robinson William H , Holers V. Michael , Kuhn Kristine A 
Published: February 2023

Abstract
A wide array of data supports rheumatoid arthritis (RA) as a disease with mucosal origins, including presence of IgA RA-associated autoantibodies in peripheral blood and biomarkers of inflammation at mucosal sites. Individuals at-risk for developing RA, (serum autoantibody+, without joint disease), can be characterized by an expansion in dual-family IgA/IgG circulating plasmablasts. We examined the characteristics of mAbs generated from these plasmablasts in at-risk (n=4) and early RA (&lt;1 year from diagnosis, n=2) subjects. The variable regions of the plasmablasts were sequenced and clonal families mapped. 94 total heavy and light chain sequences were cloned into a mouse IgG2a constant region. All 94 expressed mAbs bound RA-related citrullinated/uncitrullinated synovial targets in an antigen array, demonstrating polyreactivity. As these mAbs were derived from IgA-containing clonal families, we queried if they have commensal bacterial targets by exposing them to a human fecal bacterial pool. 61.7% of mAbs had bacterial targets, suggesting additional polyreactivity. Bound bacteria were 16S rRNA sequenced. Interestingly, 56.31% ±12.85 of bound bacteria were of families Lachnospiraceae/Ruminococcaceae. A smaller subset of Vh genes were utilized among bacterially reactive plasmablast mAbs as compared to the wider population, though mutations from germline remained static between groups. Specifically, mAbs utilizing IgHV4-4, V3-64, V3-66, and V3-74 were bacterially reactive, and mAbs utilizing IgHV4-39, V4-59, V3-33, and V3-43 were not bacterially reactive. This demonstrates a link between mucosal and systemic immune systems in RA, suggesting an early mucosal trigger for disease-specific autoantibody development.
A critical CTCF binding site of the Ifng-Il22 locus specifies cytokine expression and finetunes immune response
Authors: Shih Han-Yu , Liu Chunhong , wang ping , Signorella Sadie , Montgomery William , Jankovic Dragana , Nagashima Hiroyuki , Yao Chen , Kanno Yuka , Ryan Yijun , O’Shea John J 
Published: February 2023

Abstract
Precise control of cytokine milieu plays an essential role in homeostasis and diseases, and dysregulated cytokine production leads to undesired inflammation and autoimmunity. Interferon gamma (IFN-γ) and interleukin-22 (IL-22), two key cytokines for against intracellular and extracellular pathogens, respectively, evolutionarily resides in close genomic proximity. Notably, these genes are exclusively expressed in type I and type III lymphoid cells via complex epigenomic regulation that remains largely unknown. Our ATAC-seq, ChIP-seq and PollI ChIA-PET datasets revealed a CTCF binding site 70kb upstream of Ifng setting a boundary of the enhancer landscapes. Therefore, we proposed that this CTCF site segregates Ifng and Il22gene enhancers for lineage-specific gene regulation. To investigate whether this CTCF binding contributes to bifurcated cytokine gene regulation at the Ifng-Il22 locus, we deleted this 17bp Ifng (−70kb)CTCF site in mice using a CRISPR strategy. We found that Ifng (−70kb)CTCFdel CD4+ T cells revealed deficiency in initial Th1 cell differentiation. Using single cell RNA-seq and Toxoplasma gondii infection as a model for type I immune response in vivo, we identified aberrant Th17 differentiation and increased T cells prolifereation in Ifng (−70kb)CTCFdel mice. To further understand the molecular mechanism, we measured CTCF associated loop formation in pre-differentiated Naïve CD4+ T cells and interestingly, this Ifng (−70kb)CTCF site formed a loop with a CTCF-enriched region on the other side of Il22 gene. Our data provide a novel pre-determined mechanism that prevents cross activation for IFN-γ enhancers to target IL-22 prior to differentiation.
Immunology education within an undergraduate program for Health Sciences education
Authors: Sika-Paotonu Dianne , Patel Jennika , Reed Katie , McTavish Arthur , Humphries Felix , Motu Lakin 
Published: February 2023

Abstract
Immunology education remains an essential component for undergraduate Health Sciences education across the health professions. The clinical relevance of Immunology teaching can be emphasised by utilisation and appropriate reference to pertinent health conditions affecting populations locally and across the global setting. Health issues of significance to Māori and Pacific populations groups in Aotearoa/New Zealand and in the Pacific Region include Cancer and Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD). ARF is the body’s autoimmune response to untreated Group A Streptococcal (GAS) infection of the throat or skin. If left untreated, repeated or severe ARF episodes can lead to permanent cardiac damage known as RHD. RHD is a significant cause of morbidity and mortality worldwide. The growing global burden of cancer remains of concern, while Pacific Peoples and Māori are disproportionately affected by specific cancers. The utilisation of two areas with strong Immunological relevance for teaching examples in undergraduate Health Sciences education were shown to support improved understanding, class participation, topical interest, and research focus for Medical students engaged within Health Sciences education platforms in Aotearoa/New Zealand. This highlights the value of supporting Immunology education efforts by incorporating appropriate reference to pertinent health conditions relevant to populations groups locally and across the global setting.
Hematopoietic protein RELT stains prominently in breast cancer and binds the cytoskeletal protein Filamin A.
Authors: Cusick John K , Yanumula Anusri , Alhomsy Yasmeen , Bilasy Shymaa , Aghaians Dino , Gillespie Brittany , Senderovich Michelle , Zhou James , Wang Wenjia , Wong Stephanie , Shi Yihui , Hejazi Nazila 
Published: February 2023

Abstract
Receptor Expressed in Lymphoid Tissues (RELT) is a human TNFR superfamily member expressed most prominently in cells and tissues of the hematopoietic system. Mouse knockout studies indicate that RELT functions in part by negatively regulating T-cell activation. RELT has two homologous binding partners, RELL1 and RELL2, and collectively, these proteins are described as RELT family members. This study sought to identify novel protein interactions with RELT family members and to compare the expression of RELT in normal and diseased tissues. A yeast two-hybrid screen utilizing RELL1 as bait identified the cytoskeletal protein Filamin A (FlnA); physical interaction between FlnA and RELT family members was confirmed by in vitro co-immunoprecipitation. A truncated mutant of FlnA disrupts the ability of RELT family members to activate the p38 pathway. Previous reports indicate that autoantibodies against RELT are associated with breast cancer and that RELL2 prevents migration and invasion of the metastatic breast cancer cell line MDA-MB-231 (231), while multiple studies suggest a link between FlnA and breast cancer. We therefore sought to examine the association of RELT family members with breast cancer. Western blotting revealed significant expression of endogenous RELT family members in the breast cancer cell lines 231 and MCF-7. Immunohistochemistry (IHC) revealed a higher intensity of RELT staining in breast cancer tissues versus normal mammary tissue. Additionally, overexpression of RELT family members enhanced apoptosis in 231 cells. Collectively, these results further our understanding of signal transduction pathways associated with RELT family members and provide evidence that RELT is upregulated in breast cancer.
Nutrient partitioning in the tumor microenvironment
Authors: Madden Matthew Z , Reinfeld Bradley I , Wolf Melissa M , Chytil Anna , Cohen Allison S , Muir Alexander , Hongo Rachel A , Abraham Abin , Beckermann Katherine E , Manning H Charles , Rathmell W Kimryn , Rathmell Jeffrey C 
Published: February 2023

Abstract
The tumor microenvironment (TME) includes cancer and infiltrating immune cells. Tumors canonically consume glucose through Warburg metabolism, a process forming the basis of cancer imaging by positron emission tomography (PET). Activated immune cells also rely on glucose, and impaired immune cell metabolism in the TME contributes to tumor progression. It remains uncertain, however, if immune cell metabolism is dysregulated in the TME by cell intrinsic programs or by competition with cancer cells for limiting nutrients. Here we used PET tracers to measure access and uptake of glucose and glutamine by specific cell subsets in the TME. Surprisingly, myeloid cells had the greatest capacity to uptake glucose in vivo, followed by T cells and cancer cells across a range of cancer models. Cancer cells, in contrast, demonstrated high glutamine uptake. This distinct nutrient partitioning was cell intrinsically programmed through mTORC1 signaling and glucose and glutamine-related gene expression. Inhibiting glutamine uptake enhanced glucose uptake across tumor resident cell types, suggesting that glutamine metabolism suppresses glucose uptake without glucose being limiting in the TME. Thus, cell intrinsic programs dictate the preferential immune and cancer cell acquisition of glucose and glutamine. Cell selective partitioning of these nutrients may be exploited to develop therapies and imaging strategies to enhance or monitor the metabolism and activities of specific cell populations in the TME.
Developing natural killer cells producing hypoxia-inducible cytokines for effective immunotherapy against solid tumors.
Authors: Jo Dong-Hyeon , Lee Seung-Hwan 
Published: February 2023

Abstract
Natural Killer (NK) cells are a promising means for adoptive immunotherapy for cancers. NK cell therapies against hematological cancers such as acute myeloid leukemia have demonstrated good efficacy. However, the poor effector function of tumor-infiltrating NK cells limits the potential of NK cells against solid tumors. Accumulating data suggests that hypoxia in the tumor microenvironment (TME) suppresses the effector function of NK cells. One of the immunosuppressive features of hypoxia is the generation of adenosine, a metabolite that highly suppresses NK cell cytotoxicity and proliferation. Although engineering NK cells to overexpress stimulatory cytokines before the adoptive immunotherapy has demonstrated promising potential for cancer therapy, it raises a concern that high systemic levels of cytokines may lead to cytokine-mediated pathology. Therefore, we hypothesize that driving overexpression of the potent stimulatory cytokines exclusively in the TME would circumvent systemic toxicity. An attractive strategy to achieve this goal is to take advantage of the hypoxic condition, a key characteristic of the TME. Hypoxia-inducible factor 1 alpha (HIF1-α) plays a pivotal role in expressing hypoxia-responsive genes by associating with promoters containing hypoxia response element (HRE). By mimicking the biological system, HRE-induced cytokine expression vectors were generated and tested in NK cells. The expression was inducible under hypoxic conditions and was reversible upon re-oxygenated conditions. Our results suggest that the hypoxia-inducible vector system can be beneficial to trigger TME specific cytokine expressions in NK cells and provide insight into efficient immunotherapy against solid tumors.
Modulation of CD8+ T cell antitumor function by an immune inhibitory molecule sushi domain containing 2
Authors: Zhao Bao , Gong Weipeng , Wen Haitao 
Published: February 2023

Abstract
A central mechanism by which the immunosuppressive tumor microenvironment (TME) facilitates tumor growth is the inhibition of CD8+ effector T cell function. Indeed, restoration of CD8+ T cell antitumor functions by immune checkpoint blockade (ICB) treatment represents a significant breakthrough in cancer therapy. However, a major challenge remaining in ICB immunotherapy is the existence of multiple immune checkpoint molecules. As a result, targeting of a single molecule cannot override compensatory signals from other immune inhibitory molecules. Therefore, there is an urgent need to identify new therapeutic target(s) to rejuvenate CD8+ T cell antitumor immunity for cancer therapy. Through unbiased gene profiling assay, our recent study has identified SUSD2 (sushi domain containing 2) as a highly expressed immune cell-associated cell surface molecule in an experimental cancer model. Using a newly developed Susd2 gene-deletion (Susd2−/−) mouse model, we found that genetic deletion of Susd2 led to an improved control of tumor growth in syngeneic tumor models including colorectal carcinoma MC38 and thymoma EG7. This improved tumor control phenotype of Susd2−/− mice required the presence of CD8+ T cells. Single-cell RNA sequencing assay revealed increased production of effector molecules such as granzyme B (Gzmb) and interferon (IFN)-γ in tumor-infiltrating CD8+ T cells from Susd2−/− mice compared to those from wild-type (WT) mice. Mechanistically, we found that SUSD2 negatively regulated IL-2 receptor (IL-2R)-mediated generation of Gzmb and IFN-g in CD8+ T cells. In sum, our results identify SUSD2 as a new immune inhibitory molecule which can be targeted to augment CD8+ T cell antitumor response.
High grade gliomas impact cell fate differentiation of hematopoietic stem and progenitor cells in the bone marrow
Authors: Dean Bayli DiVita , Wildes Tyler , Dean Joseph , Shin David , Francis Connor , Font Laura Falceto , Moore Ginger , Fernandez Brandon , Wummer Brandon , Kuizon Carmelle , Mitchell Duane , Flores Catherine 
Published: February 2023

Abstract
Glioblastoma (GBM) remains a deadly disease with an overall survival of 18 months. Despite advances in cancer immunotherapy, especially in the context of solid tumors derived outside of the central nervous system, GBM remains difficult to treat. This may be due, in part, to reduced T cell function and expansion of suppressive myeloid cells within the periphery. Here we sought to determine if GBM impacts the phenotype and gene expression of progenitor populations within the bone marrow where hematopoietic stem and progenitor cells (HSPCs) originate.
Using RNAseq, we found HSPCs derived from intracranial glioma-bearing mice possess altered gene expression relative to HSPCs derived from non-tumor-bearing mice. In addition, we found glioma-bearing mice possess an expansion of myeloid-derived suppressor cells (MDSCs) within their bone marrow and are significantly more suppressive on T cell proliferation and T cell-mediated tumor cell killing than MDSCs isolated from non-tumor-bearing mice. We also determined HSPCs derived from glioma-bearing mice are more likely to differentiate into MDSCs than HSPCs derived from non-tumor-bearing mice.
Interestingly, we found components of immunotherapy are capable of redirecting cell fate differentiation of glioma-bearing HSPCs. We determined HSPCs cultured in T cell supernatants are capable redirecting their differentiation from suppressive MDSCs towards stimulatory DCs. Finally, using two murine glioma models, we found adoptive cellular therapy using HSPCs derived from glioma-bearing mice is capable of providing a similar survival benefit as adoptive cellular therapy using HSPCs derived from non-tumor-bearing mice.
Probing the naturally acquired immune response to malaria for broadly reactive antibodies targeting P. falciparum antigens linked with severe disease
Authors: Reyes Raphael , Turner Louise , Ssewanyana Isaac , Rek John , Greenhouse Bryan , Bol Sebastiaan , Lavstsen Thomas , Bunnik Evelien 
Published: February 2023

Abstract
Severe malaria is caused by the adhesion of Plasmodium falciparum-infected erythrocytes to host receptors on vascular endothelium. Specifically, binding of the parasite variant surface antigen domain CIDRa1 to host endothelial protein C receptor (EPCR) is strongly associated with severe disease. In malaria-endemic regions, children quickly develop immunity against severe malaria, indicative of the development of an effective immune response against CIDRa1 domains. Indeed, serum IgG from naturally immune individuals exhibited reactivity against a diverse panel of CIDRa1 variants. In an effort to analyze CIDRa1 antibody responses at a monoclonal level, we isolated CIDRa1-specific memory B cells from malaria-experienced individuals living in Uganda and expressed the corresponding monoclonal antibodies (mAbs). Our approach has yielded anti-CIDRa1 mAbs ranging in breadth from variant-specific to reactive with the full spectrum of CIDRa1 domain variants, irrespective of their extensive sequence diversity. The broadest antibodies can be separated into two categories, those that bind outside the EPCR binding site and display exceptional breadth with modest inhibition of EPCR binding and those that target the EPCR binding site and show potent EPCR-binding inhibition. Two EPCR-binding site-targeting mAbs isolated from two different donors showed signs of convergent evolution. Our results demonstrate that natural P. falciparum infection can induce a broad and inhibitory antibody response against CIDRa1. Current experiments are aimed at understanding the structural basis of antibody-mediated inhibition of CIDRa1-EPCR binding to inform the design of a vaccine that protects against severe malaria.