bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence similarity between SARS-CoV-2 Nucleocapsid and CNS proteins provides mechanistic insight into viral neuropathogenesis following infection
Authors: Lake Camille , Breen Joseph 
Published: January 2023

Abstract
The novel coronavirus SARS-CoV-2 emerged in 2019 and continues to cause death and disease throughout the world. To date, there have been 272 million infections and 5.3 million deaths worldwide, underscoring the necessity of understanding the virus and host immune response as well as developing novel therapeutics for severe disease. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies – including cases similar to Multiple Sclerosis (MS) - has emerged that suggest a related, underlying mechanism of viral mimicry to proteins expressed by CNS tissues. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins typically associated with MS. Using Pepmatch, a bioinformatics package which predicts peptide similarity in the context of MHC presentation, we discovered that Nucleocapsid protein, but not Spike or Membrane proteins, of SARS-CoV-2 shares significant overlap with 22 MS-associated proteins. To provide further physiological relevance, we used an MHC binding prediction tool to determine whether these Nucleocapsid peptides would bind preferentially to MS-associated alleles. While we did not find any significant binding pattern among MS-associated alleles, we did discover that Nucleocapsid peptides which overlap with CD99 Antigen were among the top HLA-peptide predictions. This finding provides a plausible mechanism by which the targeting of CD99 by lymphocytes leads to compromised blood-brain-barrier integrity and exacerbated viral neuropathogenesis. This work provides a deeper understanding of the unique viral dynamics with the human immune system and corroborates the targeting of CD99 to ameliorate neurological complications of SARS-CoV-2.
Molecular chaperone GP96 is a potential target to modulate dendritic cell programming and shape anti-tumor immunity
Authors: Mazzoccoli Luciano , Iwanowycz Stephen , Peterson Chelsea , Ngoi Soo , Hill Megan , Liu Bei 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen-presenting cells providing costimulatory signals to adaptive immune cells. Currently, the lack of strategies to improve antigen presentation is a hindrance in tumor immunology. Despite studies focusing on antigen cross-presenting Type-1 DCs (DC1s), a study published by our lab revealed Type-2 DCs (DC2s) with significant survival across multiple human cancers. Our research group has a long-term interest in studying immune chaperone GP96, which is an essential molecular chaperone for TLRs, GARP, and other vital innate receptors. The immune-related client network of GP96 creates opportunities to unmask the roles of multiple receptors on DCs. We have generated DC-specific GP96 deficient mice and reported increased tumor-infiltrating DC2 and delayed tumor development on the spontaneous breast cancer model. However, the mechanism by which GP96 regulates DCs function is under investigation. Using different tumor models, we found that deletion of GP96 on DCs improved immune response and decreased tumor growth. However, macrophage-GP96KO mice showed a loss of benefits observed on DC-GP96KO mice. Also, differential stimulatory/inhibitory molecules on DC1 vs. DC2 were tumor-dependent. To determine the role of DC-intrinsic GP96 in T cell activation, we used in vitro antigen-cross presentation assay. We found that OT-I CD8+ T cell activation was delayed at the initial days of the co-culture with GP96KO DCs but restored in the late phase compared with WT DCs. Collectively, the results show beneficial inflammatory DC2 molecular activation, with DC1 able to cross-present antigens to CD8+ T cells. Our study indicated that targeting GP96 on DCs may contribute to shaping T cell anti-tumor immunity.
Supported by grants from NIH NCI (R01:CA193939) and NIH NIAID (U01:AI125859)
B cell subsets contributing to the autoreactive plasma cell pool in Lyn−/− mice
Authors: Satterthwaite Anne B , Schneider Jalyn , Ottens Kristina 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is characterized by autoantibodies (autoAbs) against nucleic acid containing antigens. These antibodies form immune complexes that promote inflammation and cause organ damage. Defining B cell subsets that give rise to these autoAbs may reveal therapeutic approaches for SLE that spare responses to foreign antigens. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus-like autoimmune disease characterized by a large increase in autoreactive plasma cells (PCs). We used several strategies to identify the origin of these PCs. We used fate mapping to assess the contribution of T-bet+ age associated B cells (ABCs), a subset that is increased and thought to be pathogenic in both murine and human lupus. 40% of splenic PCs in Lyn−/− mice were derived from T-bet expressing cells, a significant increase compared to wild type mice that was not seen in the bone marrow PC population. Marginal zone (MZ) B cells, also implicated in some lupus models, are enriched in autoreactivity, prone to PC differentiation, and reduced in Lyn−/− mice. We hypothesized that this reduction might be due to their unchecked transit to the PC stage. However, impairing MZ B cell development in Lyn−/− mice did not reduce autoAbs. Nor did preventing PC differentiation restore MZ B cell numbers. Instead, Lyn−/− mice accumulated B1a cells when PC differentiation was impaired. B1a cells tend to be polyreactive or weakly autoreactive and are primed for terminal differentiation. Our results suggest that both ABCs and B1a cells, but not MZ B cells, contribute to the autoreactive PC pool in Lyn−/− mice. Future studies will assess the role of these subsets in the development of autoimmune disease.
Supported by grants from the NIH (R21 AI161307, R21 AI137746)
NADPH oxidase-derived superoxide promote autoreactive T cell infiltration into islets of prediabetic NOD mice.
Authors: Blum Samuel I , Barra Jessie , Baker Rocky , Tse Hubert Ming 
Published: January 2023

Abstract
Proinflammatory cytokines, reactive oxygen species (ROS), and T cells contribute to β-cell destruction in Type 1 diabetes (T1D). NADPH oxidase (NOX) generate superoxide, a precursor for a variety of ROS, regulate cell survival, differentiation, signaling, and autoimmune responses in T1D. Previously, we demonstrated that NOX-derived superoxide increase chemokine synthesis and skew macrophages and T cells towards an inflammatory response in T1D. However, it is unclear if NOX is required for diabetogenic T cell trafficking to islets. Using non-obese diabetic (NOD) mice deficient in NOX-derived superoxide (NOD.Ncf1m1J), we tested the hypothesis that loss of NOX-derived superoxide delays T1D by impairing autoreactive T infiltration of islets. Female NOD. Ncf1m1J mice (n=20) exhibit a significant delay in spontaneous T1D, as only 20% become diabetic by 40-weeks of age compared to 90% NOD mice (n=23). Immunophenotyping of 12-week-old NOD.Ncf1m1J mice revealed fewer pancreatic CCR2+ CD4+ (1.9-fold) and CCR5+ CD4+ T cells (2.1-fold) compared to NOD. NOD.Ncf1m1J islets also had reduced total CD4+ (1.8-fold), CD25+ CD4+(2.0-fold), and effector CD4+ T cells (2.2-fold) compared to NOD. Using tetramer staining to detect autoreactive T cells, we observed a decrease in NOD.Ncf1m1J islet-infiltrating CD4+ T cells specific for insulin (Ins) (2.6-fold), Ins-chromogranin A hybrid peptide (HIP) (3.0-fold), and Ins-islet amyloid polypeptide HIP (2.6-fold) compared to NOD. Our data provides evidence that loss of NOX-derived superoxide can impair autoreactive T cell activation and islet-infiltration as a potential mechanism to delay T1D. Future studies will determine if NOX regulates islet chemokine synthesis to induce T cell migration.
Supported by R01 DK126456 R01 DK127497 T32 GM109780 T32 AI007051 F31 DK130551
Regulation of T cell CD5 levels by BTLA
Authors: Adegoke Adeolu , Šedý John R , Ware Carl F , Baldwin Troy A , Anderson Colin C 
Published: January 2023

Abstract
Many coinhibitory receptors are absent from naïve T cells and upregulated upon activation. In contrast, there are a small number of coinhibitory receptors expressed constitutively by naïve T cells, including CD5, BTLA, and VISTA. The relationship between these constitutively expressed coinhibitors is unknown. We examined the relationship between the constitutively expressed BTLA and CD5 in T cell ontogeny. We found an inverse relationship between CD5 and BTLA expression levels, with low BTLA expression in the thymus and higher BTLA expression in the periphery, corresponding with high and low CD5 expression, respectively. To determine if there is a causal relationship between BTLA expression and CD5 expression, we examined CD5 expression in wild type (WT) vs. btla−/− T cells. Interestingly, btla−/− T cells consistently expressed higher levels of CD5 both in thymic and splenic CD4 and CD8 T cells, indicating that BTLA expression directly or indirectly determines the level of CD5 expression broadly across T cells. In contrast, the loss of an inducible coinhibitor, PD-1, only affected CD5 levels on splenic CD8+ T cells. The loss of BTLA expression early in ontogeny might alter the TCR repertoire indirectly affecting CD5 levels, or instead its loss might affect CD5 expression rapidly within mature T cells. To examine the latter, we deleted btla by administering tamoxifen to adult btlafl/fl CreERT2+/− mice and WT CreERT2+/− controls. Loss of btla in adults led only to a transiently heightened CD5 expression. Together our data indicates that loss of BTLA early, but not later in ontogeny, leads to a long-term increase in CD5 expression by T cells. Such calibration of CD5 levels early in ontogeny might serve to reduce autoimmunity.
Funded by the CIHR, NSERC, and an AAI fellowship; btlafl/fl mice provided by the La Jolla Institute for Immunology.
Identification of the brain network controlling systemic inflammatory signals
Authors: Hashimoto Okito , Lee Diana , Hepler Tyler , Tsaava Tea , Tynan Aisling , Tracey Kevin J , Chavan Sangeeta S 
Published: January 2023

Abstract

Objective
Systemic inflammatory conditions are finely controlled not only by the immune system but also by the neuronal system in the body. While the vagus nerve is the key neuronal pathway to control the peripheral immune system, known as the inflammatory reflex, it is largely unknown how the brain regulates the reflex. The purpose of this study is to clarify the brain network response to systemic inflammatory signals.

Methods
Transgenic targeted-recombination-in-active-populations (TRAP2) mice that expressed tamoxifen-inducible Cre under control of an activity-dependent c-Fos promoter were crossed with a Cre-dependent tdTomato reporter line. These mice (TRAP2/tdTomato mice) were injected with 4-OHT (an active form of Tamoxifen) to induce Cre recombination and tdTomato expression. 30 min later, TNF was administered intraperitoneally to these mice and the brains were collected 7 days after the induction.

Results
Nucleus of the solitary tract (NTS), where vagal afferents ascending from peripheral tissues synapse on neurons, showed the increased number of tdTomato-expressing cells. In addition, TNF stimulation reinforced the tdTomato expression in the paraventricular nucleus (PVN) and the bed nuclei of the stria terminalis (BNST). Interestingly, many tdTomato-expressing cells colocalized with the sub-nuclei of PKC delta-positive neurons within the BNST.

Conclusions
Systemic TNF signals are transmitted to the brain regions through the vagus nerve, including NTS, PVN, and BNST. Furthermore, the specific neuronal population within the BNST may play a role in the modulation of systemic inflammatory condition.
This experiment is supported by grant from NIH to KJT and SSC
Supported by grants from NIH (R01GM132672, R35GM118182-01)
Using Team Based Learning to Solidify Immunology Concepts
Authors: Turula Holly , Bauler Timothy 
Published: January 2023

Abstract
Using Team-Based Learning (TBL) in the classroom allows learners to synthesize complex information to solve real-world problems. Through TBL learners distill the most salient points and draw them together in a way that fosters higher order thinking. Similarly to immune cells, we work most effectively in collaboration. During TBL learners simulate complex situations and participate in peer teaching and learning. In these ways TBL fosters mentorship and a sense of community. Not only that, but learners enjoy it and find it beneficial! Learning how to implement TBL in the classroom to help engage the learners benefits not only the student, but the professor, the institution, and the field of Immunology.
Instagram-a non-conventional learning tool in post-covid educational world. Repurposing of an entertainment app.
Authors: Fazal Nadeem , Brehm Danielle , Alakbarova Gulgaz , Huseynbayli Ayshan , Garajayev Azer , Safarova Arzu , Cebiyev Nihat , Meher Satish , De Herde Laura 
Published: January 2023

Abstract
Who would have thought that social media will ever be employed as a non-conventional learning tool. Before March 2020 everybody would have raised eyebrows and shunned the practice of even going in that direction. Pandemic changed the world! A tool of pure entertainment and pleasure had a positive effect on the generations “Z” and “X”. Little did the educators realize that one of the most intrinsic tool of self-directed learning is to stay “relevant” stay “motivated: and staying “alive” in a COVID-19 deadly environment was an app called “Instagram”. We conducted a global survey from university students across Asia, Europe, Russia, and Americas. In the current study we used “instagram” as a tool to collect anonymous data from more than 500 respondents and summarized the following points. Firstly, 80% of the respondents were females, and between the age group of 15–25 years. Only 9% reported negative mental health issues while the rest of respondents reported a positive, competitive, and highly focussed group of students who helped each other in small or large social circles to keep reminding each other of educational needs, helping with difficult assignments, and small group studying and quizzing each other. 50% of the respondents reported to get more work accomplished by communicating through messaging, pictures and videos. There was a small 10% of the students who got distracted and sometimes would get carried away but still performed well in learning objectives as compared to those who did not join the trends. 30% of the students did notice impulsiveness, increased anxiety and burnt out by excessive multitasking. Overall, we report that the best purpose for the use of instagram may not be a tool in teachers locker but definitely a peer-mentoring source.
“The Great College Escape”-the most difficult choice offered to COVID-19 generation of global students.
Authors: Fazal Nadeem , Cebiyev Nihat , Alakbarova Gulgaz , Huseynbayli Ayshan , Garajayev Azer , Safarova Arzu , Meher Satish , De Herde Laura 
Published: January 2023

Abstract
The much hyped “Great Resignation” in the world of economic forecasting has opened a big door for the students to take an easy and timely exit from education. Is it a revolving door or a one-way exit with no easy return. There are more job openings for unskilled workers, luring students to leave their studies incomplete and take over odd jobs. Remote education experience changed hearts and minds of the global students and created a survival mindset. Pandemic without question has caused significant loss of lives with profound disruption to lives and livelihoods. As the pandemic is lingering on with uncertainty and ambiguity, students are tempted to leave studies in search of more money, more flexibility, and more happiness. With the fallout of COVID-19 yet to be fully realized and fixed, the predictive-enrollment models that traditionally used to plan classes won’t hold up in the post-pandemic world. We surveyed the current student population across different continents, Asia, Europe, Russia, US and tried to figure out the mindset of student enrollment and attrition. The perception and trends data from 300 respondents across the globe showed a significant economic impact on international students failing to register for higher education abroad in western hemisphere. Majority of students surveyed believe that the education system may have oversold the value of remote education and classroom technology. Free and open-source technologies available to both teachers and students have created a monster of virtual global education. For students in Eastern part of the world, the pandemic has offered new perks. Most students reported that they are rethinking their education needs and reimagining how knowledge and learning could best shape their careers.
Novel insight into the role of the vitamin D receptor in the development and function of the immune system
Authors: Arora Juhi , Wang Jinpeng , Weaver Veronika , Cantorna Margherita T 
Published: January 2023

Abstract
Immune cells express the vitamin D receptor (VDR) and are therefore vitamin D targets. The VDR protein can be readily measured in the kidney using antibodies to the VDR and western blot. It is much more difficult to measure VDR protein in the spleen because of the low level of VDR expression in resting immune cells. In order to more sensitively measure VDR expression, the Cre enzyme was inserted in the 3rd exon of the VDR gene and a reporter mouse that irreversibly expresses tdTomato was made. Mice that express one copy of the VDRCre gene were confirmed to be VDR +/− and mice that express two copies were confirmed to be VDR −/−. Initial characterization of the immune cells from the VDR +/− VDRtdTomato+ compared to VDR+/+ wildtype (WT) littermates showed no effect of being hemizygous for the VDR on immune cell frequencies. Immune precursors from bone marrow and thymus showed high tdtomato expression. In the periphery, monocytes, neutrophils and macrophages had very high tdTomato+ (88–98%) expression while lymphocytes ranged from 60–70% tdTomato+. Tissue resident innate lymphoid cell (ILC) 1 and 3 cells were about 60–80% tdTomoto+, while ILC2 cells had very low tdTomato expression. Stimulation of VDRtdTomato+ splenocytes showed that the tdTomato− CD4+ and CD8+ T cells proliferated more than their tdTomato+ counterparts. Sorted tdTomato+ T cells expressed the VDR protein only after 72h post-activation and proliferated less than the tdtomato− T cells. Interestingly, activation of the tdTomato− T cells failed to induce new tdTomato expression. The data suggest that an early immune precursor expresses the VDR. In the periphery, neutrophils and monocytes are almost all tdTomato+, while some immune cells (ILC2 and some T cells) may never express the VDR.
Supported by NIH R01AT005378 to MTC and T32GM108563 to JA, USDA NIFA award PEN04771 to MTC.
Retention of epigenetic and transcriptional memory among reprogrammed T cells (T-iPSCs) imparts selective advantage for T cell re-differentiation.
Authors: Williams Robin L , Morrow Alyssa , Allred Jeremy , Tolar Jakub , Haining W Nicholas , Yosef Nir , Blazar Bruce R 
Published: January 2023

Abstract
Various somatic cell types reprogramed into induced pluripotent stem cells (iPSCs) can be differentiated into T cells. It remains unclear what impact the input cells reprogramed into iPSCs have on T cell differentiation. We hypothesized that preservation of T cell genetic and/or epigenetic memory would bias iPSC clones toward T cell differentiation. CD8 naïve T cells (TN), CD8 stem memory T cells (TSM), and fibroblasts (FB) were reprogramed into iPSCs using nonintegrating Sendai virus to deliver Yamanaka factors. Input cells and iPSC clones were subjected to RNA-seq and ATAC-seq to assess whether epigenetic and transcriptomic memory are retained after reprogramming. Pluripotent associated genes (NANOG, LIN28A/B, SOX2) had increased expression in both T cell− and FB-iPSCs compared to their cells of origin. Of interest, gene enrichment analysis of fibroblasts and FB-iPSCs identified fibroblast related annotations, including migration and growth factors, in reprogramed iPSCs. Among CD8 TN− and TSM-iPSCs as a group, expression of only 41 genes and 6 genomic regions were retained, but these included known mature T cell genes, CD3ɛ, ZBTB7B, and CD95 as well as a region crucial for T cell signaling. Therefore, although much of the transcriptome and accessible genome is overridden in TN/TSM-iPSCs, there exists maintenance of both the transcriptome and chromatin accessibility after reprogramming. CD8 T-iPSCs were superior to FB-iPSCs in producing T progenitors in vitro. Highlighted here is the importance of starting populations for reprogramming and differentiation into T lineage cells. Leveraging the benefits of epigenetic and transcriptomic memory of input T cells could provide a more robust source of T cells for adoptive cell therapy.
Supported in part by funds from NIH P01 CA065493 and R37 AI34495 from the National Cancer Institute and National Institute of Allergy and Infectious disease, respectively, the Childrens’ Cancer Research Fund, and Chan-Zuckerberg Biohub.
Differential therapeutic modulation of exhaustion among autoreactive and global CD8 T cells in type 1 diabetes (T1D)
Authors: Wiedeman Alice E , Vega Carolina Acosta , Serti Elisavet , Nepom Jerry , Long Alice 
Published: January 2023

Abstract
Islet-specific CD8 T cell exhaustion (TEX) is linked to slower progression of type 1 diabetes (T1D). However, in the therapeutic setting, only global TEX has been studied. Here we address whether TEX among autoreactive cells in clinical trials relates to better outcome. We assessed PBMCs from select T1D subjects who had variable preservation of pancreatic function two years after treatment with teplizumab (anti-CD3, n=7) or alefacept (LFA3-Ig, n=12). We applied a CyTOF panel incorporating pooled pancreatic islet autoantigen peptide-loaded MHC Class I tetramer and 18 phenotyping markers. CD8 T cell subsets were identified by DISCOV-R multidimensional clustering analysis and were applied to samples with &gt;5 autoreactive cells. Better clinical outcome was linked to greater frequencies of global CD8 TEX (subsets expressing PD1, EOMES, TIGIT, and KLRG1): a PD1hi subset 2 months after teplizumab (p=0.049) and a CD57hi subset 2 years following alefacept (p=0.044) treatment. Overall, increases in islet-specific TEX were rarely detected in poor responders (1 of 8 subjects with detectable islet-specific cells) consistent with a lack of change in global TEX, However, in subjects with better preservation of beta cell function, islet-specific TEX increased in fewer subjects (2 of 6) than global CD8 T cells (4 of 8). Together these results indicate that islet-specific CD8 T cells only partially mirror global CD8 responses, and further research is needed to clarify the role of exhaustion and its relation to autoreactive T cells in determining outcome in therapeutic settings.
Supported by grants from NIH (R01 AI141952) and Immune Tolerance Network (UM1AI109565).