bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cell leukemia elicits a suppressive Tr1-like CD4 T cell response that can be reversed with anti-PDL1-blockade
Authors: Venkatesh Hrishi , Tracy Sean I , Hekim Can , Knutson Todd Philip , Farrar Michael A 
Published: August 2023

Abstract
CD4 T cell exhaustion is associated with relapse in B cell leukemia (B-ALL) patients. However, checkpoint blockade is not effective in treating B-ALL. Using a murine model of B-ALL, we demonstrate that leukemia induced CD4 T cells had a unique regulatory-cytotoxic phenotype (Trctx) with preferential expression of exhaustion markers (PD1/TIM3) as well as IL10 and c-Maf, which are markers of immunosuppressive Tr1 cells. Leukemia cells acting as APCs elicited CD4 T cells with a similar Tr1 phenotype that suppressed bystander T cells. This process mimics the mechanism by which hematopoietic stem cells (HSC) enforce an immunosuppressive niche in the bone marrow that protects the HSC compartment. Anti-PDL1 or nilotinib (targeted therapy) treatment alone had a minimal impact on survival; concurrent treatment with anti-PDL1 and nilotinib had a significant synergistic effect that was dependent on CD4 and CD8 T cells. Nilotinib treatment increased markers of helper and regulatory function in the Trctx cells. In contrast, treatment with nilotinib and anti-PDL1 induced expansion of a leukemia-specific CD4 T cell clone with lower expression of Tr1 markers and higher expression of helper molecules that facilitate recruitment and activation of anti-tumor immune cells. Expansion of the helper-cytotoxic (Thctx) CD4 T cell clone was associated with increased GzmB+ CD8 T cells. We propose that leukemia coopts a naturally occurring process designed to protect the HSC niche, thereby inducing Trctx cells that drive escape from immune surveillance. Combining nilotinib and anti-PDL1 alters the balance between immunosuppressive Trctx and immune-activating Thctx, thereby inducing a protective anti-leukemia immune response that prevents relapse.
Spatial Transcriptomics Award from the University of Minnesota, Children’s Cancer Research Fund
Identification and characterization of a dominated T cell population in tumor associated antigen specific CD8+ T cells of tumor microenvironment
Authors: Chuang Ming-Kai , Lee Tsai-Heng , Chia Jean-San 
Published: August 2023

Abstract
The characteristics and roles of tumor associated antigens (TAAs) specific tumor infiltrative T cells (TILs) are not well understood. Alpha-enolase is one TAA of oral squamous cell carcinoma (OSCC) and pancreatic cancer, and are highly expressed in many cancer types by analyzing the TCGA database. We detected α-enolase responsive CD8+ T cells in peripheral blood mononuclear cells (PBMCs) and TILs of OSCC patients. The α-enolase responsive CD8+ T cells significantly increased in TILs than those in PBMCs. We developed two tetramers to identify two different α-enolase peptides specific CD8+ T cells. Two types of tetramer positive CD8+ TILs, total CD8+ TILs, and total CD8+ T cells from PBMC of three OSCC patients were sorted. Single cell RNA sequencing was performed. Unbiased clustering revealed 11 distinct CD8+ T cell clusters. To our surprise, the cell population patterns of both tetramer positive CD8+ TILs were similar, but were much different from total blood CD8+ T cells or total CD8+ TILs. The percentages of relatively exhausted T cells were similar in three TIL groups, but was nearly absent in blood. The blood CD8+ T cells had the highest percentage of effector memory T cells and naïve T cells. A specific cell cluster dominated (&gt;50% population) in the two tetramer positive CD8+ TILs. The expression of important immune related genes in the specific cell cluster were all relatively low. That hinted this T cell subset was more quiescent than other cell clusters, and may have potentials to be activated. Further clarify the roles of the special T cell subset in tumor immunology is warranted.
Supported by grants from National Science and Technology Council, Taiwan (110-2314-B-002-299)
Modeling Immunological Networks in an Educational Setting using Cell Collective
Authors: Taylor Rebekah , Pandey Sumali , Justement Louis B , Helikar Tomas 
Published: August 2023

Abstract
One challenge in the teaching of immunology is the complexity of the subject. Immunology presents a long list of unique cells, signaling molecules, receptor-ligand interactions, regulatory mechanisms, developmental pathways, and outcomes that can feel burdensome to instructors and unapproachable to students. The beauty of this subject, however, is that these unique features interact in networks that parallel those in other biological fields. Visualizing the interactions between tissues, cells, and molecules of the immune system and their outcomes can promote immunological literacy and a broad understanding of biological systems.
Cell Collective (cellcollective.org) is an open-access, approachable software system that allows students and researchers alike to build models and perform simulations of biological processes. Students can use this interactive platform to probe cell-cell interactions, signaling pathways, metabolic networks, etc. while building systems thinking and computational skills, which are critical for success in STEM fields. After building models, real-time simulations can be run to visualize and understand the dynamics of the biological system under conditions of environmental pressure, disease, mutation, etc. Instructors can assess student knowledge by building assessments into modules in a formative or summative manner. Because it is free, user-friendly, and offers a host of pre-built training, educational and experimental modules, Cell Collective is ideally suited for use in all types of educational settings.
Supported by a grant from the NSF (RCN-UBE) 2120806
Smart textbooks and LMS-integrated digital tools incentivize student engagement and facilitate learning in an undergraduate immunology course
Authors: Walline Crystal C 
Published: August 2023

Abstract
During the COVID-19 pandemic, educators were compelled to quickly pivot their face-to-face courses to a hybrid, online, or asynchronous delivery, and to develop learning management (LMS) course websites to seamlessly delivery course content, assignments, assessments, and other instructional tools. Concurrently, textbook publishers are offering LMS-integrated, comprehensive, digital solutions, including “smart” or adaptive learning electronic textbooks. W.W. Norton & Company publisher has recently released digital resources to complement the 5th edition of Peter Parham’s The Immune System, including chapter reading assignments which incorporate adaptive quizzing and gamification using the InQuizitive feature. Here, based on student responses in early questions, subsequent questions are personally curated by learning objectives and difficulty level. Instructors may customize the difficulty level and determine a minimum score to be achieved to earn the assigned points which incentivizes students to read the textbook prior to classroom meetings or discussions. Additionally, instructor resources include Case Studies in Immunology, slides and graphics, animations, activities, primary literature suggestions, and an LMS-integrated test maker. Overall, student feedback was overwhelmingly positive, grades were substantially higher compared to previous semesters, and because more students came to class prepared, classroom time was used more efficiently such that all foundational topics outlined by the AAI Education Ad Hoc Committee were delivered. Therefore, LMS-integrated, adaptive learning textbooks are an essential component for a successful undergraduate immunology course.
Voiceover lectures and gaming; assessing student and faculty perceptions of this pedagogy and determining its effectiveness in teaching immunology and academic policies
Authors: Cusick John K , Zemeida Savannah , Chou Emily , Chang Esther , Shyu Yennie , Abram Alyssa , Gerriets Valerie 
Published: August 2023

Abstract
Our objective was to obtain feedback from students and faculty on the use of pre-recorded voiceover lectures and in-class games to determine the impact of these pedagogies on educational outcomes. To evaluate understanding of academic progression policies, matriculating medical students were given quizzes before and after participating in a review game covering these policies. To evaluate the understanding of immunology content, students were randomly placed into groups in which a quiz was given after 1) attending a traditional lecture, 2) watching a voiceover and participating in a review game, or 3) no exposure to teaching on subject. Likert scales were used to assess impressions from both students and faculty regarding this pedagogy. Survey results indicated that students who participated in a review game scored significantly higher in comparison to matriculating students who learned about academic policies solely through their orientation. Both students and faculty believe that voiceovers combined with review games is a superior educational method than traditional lectures. Although faculty believe these active learning pedagogies are more tedious to create than traditional lectures, faculty expressed an interest in adopting this pedagogy especially if training and IT support are provided. Collectively, our results indicate that faculty and students both strongly prefer the use of active learning pedagogies over traditional lectures, and student comprehension of academic policies increased significantly after participating in a review game. A significantly increased understanding of immunology content through active learning pedagogy versus traditional lectures has not yet been established in this ongoing study.
Supported by grants from the California Northstate University Institute of Teaching and Learning Excellence (ITLE).
Anti-SARS-CoV-2 IgG levels are associated with circulating levels of chemokines CXCL9/CXCL10 and severity disease, but not with RBD-specific B cells 4 months after COVID-19
Authors: Quiroga Romina Andrea , Novoa Sergio Andrés Sanhueza , Cabrera-Garcia Camilo Daniel , Cáceres Bárbara Evelyn Antilef , Munoz Camila Paz , Llerena Faryd , Fraga Marco , Henriquez Mario , Labarca Gonzalo , Nova-Lamperti Estefania , Colombo Alicia , Fernandez Liliana Lampert 
Published: August 2023

Abstract

Background
It has been reported that the humoral response and cytokine secretion is exacerbated in patients with severe COVID-19. However, it is unknown which cytokines are associated with the exacerbated humoral immune response during and after COVID-19. The aim of this study was to determine the association between cytokines and the humoral response of patients who had COVID-19 with different severity degree.

Methods
60 COVID-19 patients were recruited from Víctor-Rios-Ruiz Hospital during acute phase and at 4-months post-infection. Clinical exams were performed to evaluate lung damage after COVID-19. Serum samples were collected to measure IgG levels (Nucleocapsid + Spike) using commercial CLIA assays and cytokines and chemokines by Cytometric Bead Array (CBA). The percentage of B cell subsets and RBD-specific B cells were measured by flow cytometry.

Results
Anti-SARS-CoV-2 IgG levels, but not RBD-specific B cells, were significantly associated with severity and pulmonary sequelae. Moreover, the data revealed that proinflammatory chemokines CXCL9 and CXCL10 were significantly correlated with Anti-SARS-CoV-2 IgG levels. We also observed that these chemokines promote CD40L upregulation and B cell differentiation into plasma cells.

Conclusions
Severe COVID-19 patients produced higher anti-SARS-CoV-2 IgG levels than patients with mild disease, possibly due to an exacerbated immune response, associated with sustained levels of proinflammatory chemokines CXCL9 and CXCL10. This exacerbated response was associated with structural lung damage post-COVID-19.

COVID1005 project Fondecyt Regular 1211480 ACT210085
Elevated C-reactive protein and depression score among post-COVID-19 patients - A cross-sectional study
Authors: Giridharan Vijayasree Vayalanellore , Cardoso Taiane de A , Silva Ritele H , Fernandes Jessica L , Arent Camila O , Amboni Graziela , Borba Laura A , Padilha Alex Paulo Z , Botelho Maria Eduarda M , Maciel Amanda L , Soares Silvio José B , Bagatini Margarete D , Dallagnol Claudia , Brighenti Marta Elisa , Ignácio Zuleide Maria , Quevedo João , Ceretta Luciane B , Morales Rodrigo , Barichello Tatiana , Reus Gislaine Zilli 
Published: August 2023

Abstract
Immune dysfunction after SARS-CoV-2 infection leads to long COVID neurological sequels in COVID-19 survivors. Despite initial respiratory symptoms, neuropsychiatric manifestations have been reported in many COVID-19 patients. We aimed to investigate the psychological symptoms, gut microbiome status, and C-reactive protein levels (CRP) in post-COVID individuals. This cross-sectional study included age and sex-matched individuals with post-COVID (n = 114) or controls (n = 236). We used Mini International Neuropsychiatric Interview (MINI) to diagnose psychiatric disorders. The depressive and anxiety symptoms were assessed by the Hamilton Rating Scale and the stress level by an inventory of stress symptoms and circulating CRP levels measured. In a small cohort (post-COVID = 18 and controls = 46), the gut microbiome was evaluated by 16S rRNA sequencing. Post-COVID individuals exhibited greater severity of depressive symptoms (p = 0.034), higher levels of stress (p = 0.020), and CRP (p = 0.014) as compared to controls. There was no difference in α-diversity but β-diversity (p = 0.001) was significantly different between control and post-COVID groups. Interestingly, post-COVID individuals with depression had greater CRP levels than those with COVID-19 without current major depression disorder (p = 0.023). Post-COVID-19 individuals have demonstrated severe psychological symptoms and altered gut microbiome levels. Although longitudinal studies are needed to study the mental health trajectory of COVID-19 individuals, the levels of CRP may serve as a promising biomarker for the early detection of post-COVID depression.
New Complement Dependent Cytotoxicity Assay and its application to COVID-19 patient sera harboring anti-lymphocyte antibodies
Authors: Calderon Stephanie , Liu Xiangdong , Lisco Andrea , Kellog Anela , Galindo Frances , Memoli Matthew , Rocco Joseph M , Laidlaw Elizabeth , Manion Maura , Sereti Irini , Perez-Diez Ainhoa 
Published: August 2023

Abstract
Complement dependent cytotoxicity (CDC) is one of the ways IgM and IgG antibodies can mediate the lysis of target cells, being IgM the antibody (Ab) isotype with the highest CDC activity. In a cohort of hospitalized COVID-19 patients we identified that 27% carried IgM anti-lymphocyte Ab in their sera. To quantify the sera potential lytic activity against healthy donor (HD) PBMC we developed a flow-based CDC assay with an internal negative control. The assay allows for normalization of the results and therefore inter-experiment data comparison without the need of using counting beads. In short, after CFSE labelling, 2 million PBMC are incubated with either complete media (CM) or with the different experimental conditions (Ab, sera, plasma), then they are washed thoroughly before adding them to equal numbers of unlabeled PBMC (internal negative control). This mixture of hot CFSE+ and cold CFSE-targets is then incubated with rabbit complement for an hour, stained and flow. A “ratio tube” containing the mixture with the CM incubated CFSE cells, is left without rabbit complement at 4 degrees and used to calculate the initial CFSE+/CFSE− ratio. We calculate the percentage of CDC lysis based on the CFSE+/CFSE− ratio in each tube after normalizing it to the ratio tube. Deploying this assay, we found CDC activity against B and T cells in five and two COVID-19 patients’ sera, respectively, out of 23 patients tested. This improved CDC assay shows high reproducibility and allows for quick, reliable, and easy test of multiple conditions.
This work was supported by the Divisions of Intramural Research of NIAID, NIH
Dysregulated immune networks define distinct respiratory phenotypes of post-acute sequelae of COVID-19
Authors: Canderan Glenda , Muehling Lyndsey M , Kadl Alexandra , Sturek Jeffrey , Bonham Catherine , Murphy Deborah , Lima Sierra , Cross Claire , Wilson Jeffrey , Cheon In Su , Sun Jie , Irish Jonathan , Woodfolk Judith A 
Published: August 2023

Abstract
Long-haul respiratory symptoms are common following severe COVID-19 illness; however, the immune mechanisms contributing to post-acute sequelae of COVID-19 (PASC) remain enigmatic. A comprehensive 2-year longitudinal immune assessment was performed in a cohort of PASC patients receiving pulmonary follow-up care (n=110) by analyzing circulating immune cells using spectral flow cytometry, as well as assessment of virus-specific T cell frequencies, serum antibodies, and plasma mediators. Novel unsupervised machine-learning workflows were used to analyze and integrate multiple clinical and immune measures. Our approach identified discrete respiratory phenotypes according to lung physiology measures that defined the degree of lung fibrosis and its severity. Notably, severe respiratory phenotypes were characterized by immune dysregulation of both innate and adaptive cellular components, including lower ILC-3-like cells and higher activated CD4+ and CD8+ T cells in the blood. On the other hand, all respiratory phenotypes displayed a marked loss of naïve CD8+ T cells and unswitched memory B cells compared to healthy individuals. Spike- and nucleoprotein-specific CD4+ and CD8+ T cells were more abundant in severe respiratory phenotypes. Overall, T cell-derived inflammatory cytokines, along with chemokine receptors and their relationships to cognate ligands, pointed to sustained lung-homing of pathogenic effector cells in fibrotic phenotypes. Integration of high-dimensional data defined discrete cellular and molecular immune networks that provide unconventional and novel mechanistic insight into pulmonary complications post-COVID-19.
UO1AI125056 R21 AI160334
NK cell activation provides protection against herpes simplex encephalitis through TLR3/TRIF-dependent crosstalk between epithelial and dendritic cells
Authors: Eo Seong Kug , Choi Jin Young , Byeon Hee Won , Cho Hye Won , Park Seong Ok , Uyangaa Erdenebelig 
Published: August 2023

Abstract
Herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV-1). Previous few studies have been administered on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we tried to decipher the crosstalk between type I IFN (IFN-I)-producing epithelial layer and IL-15-producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV-1 infection. TLR3- and TRIF-knockout mice showed enhanced susceptibility to HSE progression, with high HSV-1 burden in vaginal tract, lymphoid system, and CNS. The increased HSV-1 burden in TLR3- and TRIF-ablated mice did not correlate with increased infiltration of Ly-6C+ monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. In addition, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue-resident cells, such as epithelial cells in vaginal tract, found to cause impaired NK cell activation by means of low IFN-I production, whereas IFN-I receptor in DC play a role in activating NK cells via IL-15 production in response to IFN-I produced from epithelial layer. These results provide new information about IFN-I- and IL-15-mediated crosstalk between epithelial cells and DC at the primary infection site that can suppress HSE progression in a TLR3- and TRIF-dependent manner.
This study was supported by the Basic Science Research Program through National Research Foundation of Korea (NRF) grants funded by the Ministry of Education and the Ministry of Science and ICT (MSIT), Republic of Korea (2021R1A2B5B02001578, 2019R1A6A1A03033084 for Seong Kug Eo, 2020R1I1A1A01054533 for Erdenebileg Uyangaa, and 2020R1I1A2055591 for Jin Young Choi, http://www.nrf.re.kr).
Cardiac dysfunction mediators CXCL-9 and chemotaxis of phagocytes characterized patients with long-term pulmonary dysfunction after COVID-19
Authors: Novoa Sergio Andrés Sanhueza , Nova-Lamperti Estefania , Cabrera-Garcia Camilo Daniel , Quiroga Romina Andrea , Grez Camila Paz Muñoz , Cáceres Bárbara Evelyn Antilef , Labarca Gonzalo 
Published: August 2023

Abstract
Severe COVID-19 is characterized by marked cytokine release and pulmonary dysfunction; however, it is still unknown which mediators support post-COVID-19 pulmonary dysfunction. Our aim was to determine the signaling pathways associated with long-term pulmonary dysfunction in patients with COVID-19. Our cohort of 60 patients with COVID-19 were followed up at 4- and 12-months post infection. Pulmonary sequelae were analyzed by computed tomography (CT), diffusing capacity of carbon monoxide (DLCO), spirometry, 6-minute walk test (6MWT) and handgrip test. Cytokines, chemokines and blood tests parameters were also analyzed. Furthermore, signaling pathways associated with pulmonary dysfunction were identified by serum proteomics analysis using TimsTOF-Pro and ingenuity pathway analysis. Fourteen patients with CT and abnormal DLCO were classified as patients with long-term pulmonary dysfunction (LTPD), who also presented impaired spirometry tests, 6MWT and handgrip strength than patients without sequelae or patients with CT only. We observed that only CXCL-9 was significantly increased in LTPD patients in comparison with other groups. In addition, the main signaling pathways identified by proteomics in LTPD patients were associated with an immunothrombotic state related to cardiac dysfunction, migration of dysfunctional monocytes and reduced IFN-signaling. In summary, patients with LTPD presented a restrictive lung condition, with greater fatigue, lower aerobic capacity and muscle strength 4-months post-COVID-19. Our data suggest that patients with previous cardiac dysfunction who had severe o moderate COVID-19 are more susceptible to develop LTPD.
PROYECTO COVID1005, ACT210085 y Fondecyt Regular 1211480.