bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive immune response initiated by high mobility group box 1 promotes tumor progression (48.36)
Authors: Yu Ping , He Ying , Zha Jikun , Wang Yamin , Fu Yangxin , Liu Wenhua 
Published: January 2023

Abstract
Cancers are often observed to be associated with infiltrating lymphocytes. However, the role of lymphocytes in regulating pro-tumor versus anti-tumor immune responses remains controversial. We report that lymphocytes are essential for tumor progression in an autochthonous prostate cancer model. Activated T lymphocytes gradually accumulate inside the tumor during the process of de novo spontaneous tumor development driven by the tissue-specific expression of an oncogene. T cell infiltration is essential for the increased CD11b+Gr-1-F4/80+ macrophages inside the tumor. Intriguingly, blockade of high mobility group box 1 (HMGB1) drastically inhibits tumor-antigen-specific T cell activation, infiltration and tumor progression. Our study has demonstrated that “endogenous danger signals” like HMGB1 produced by a growing tumor are essential to bridge innate and adaptive immune responses, which could further promote tumor progression over time. Our finding may have important implications for future cancer prevention and therapy.
Association of inhibition of tumor growth with intratumoral hematopoiesis induced by IL-33 (48.40)
Authors: Kim Wonyoung , Kim Juyang , Kim Hyun , Cho Hong , Kwon Byungsuk 
Published: January 2023

Abstract
Immune surveillance by a functional immune system is a well-established mechanism for regulation of tumor growth. In this study, we have shown that innate type 2 helper cells (Ih2) could be an important component responsible for tumor immunosurveillance. Local production of IL-33 by lymphoma cells induces recruitment of Ih2 cells into tumor masses. In response to IL-33, Ih2 cells can proliferate, produce high levels of Th2 cytokines, and play an important role in differentiation and expansion of eosinophils in an IL-5-dependent manner. Eosinophils in turn exhibit a potent anti-tumor activity. The ability of IL-33 to induce the emergence of an Ih2 population and eosinophils in tumors identifies a link between the Th2 cytokine family member and extramedullary hematopoiesis, and suggest a previously unrecognized innate immune pathway involving lineage-negative innate cells which mediated type 2 innate immunity leading to antitumor activity
Crossreactive influenza A virus M1- and EBV-BMLF-1-specific CD8 T cells modulate disease severity of Epstein-Barr Virus-induced infectious mononucleosis (49.20)
Authors: Aslan Nuray , Watkin Levi , Luzuriaga Katherine , Selin Liisa 
Published: January 2023

Abstract
During EBV-associated infectious mononucleosis (IM) influenza A-specific crossreactive memory T cells are highly activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses cross-reacted with two different EBV lytic epitopes, BRLF-1(190) (19/20) and BMLF-1(280) (17/29). Furthermore, 11/22 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF-1 and -BMLF-1 responses. Disease severity of IM did not correlate with viral load, but instead directly correlated with the percentage of IAV-M1, EBV-BMLF-1 and crossreactive IAV-M1/EBV-BMLF-1-specific CD8 T cells. This was associated with altered TCR Vbeta usage. In all IM patients cross-reactive T cell responses were observed but different patterns of cross-reactivity were seen in each individual. A number of unique features of the TCR of the highly cross-reactive BRLF-1 epitope were noted. BRLF-1 T cell responses were of very high avidity. There was tremendous variation in the Vbeta usage between different individuals and even in the same individual over time. Cross-reactive BRLF-1 responses only became apparent at higher antigen doses in vitro, such as might occur during different phases of infectious mononucleosis.
Pathogenic H1N1 2009 influenza virus-induced pulmonary injury is suppressed by sphingosine analog-mediated inhibition of cytokine storm (49.3)
Authors: Walsh Kevin , Tiejaro John , Wilker Peter , Jatzek Anna , Suresh Marulasiddappa , Kawaoka Yoshihiro , Rosen Hugh , Oldstone Michael 
Published: January 2023

Abstract
Human pandemic H1N1 (2009) influenza virus rapidly infected millions worldwide and caused significant morbidity and mortality that was associated with cytokine storm and virus-induced cytopathology. Antiviral drugs are the primary therapy to treat disease, although there are limitations to their effective use: 1) administration must be early for optimal efficacy; 2) selective pressure is exerted on the virus resulting in the generation of viral progeny that are resistant to treatment; 3) treatment does not directly inhibit immune-mediated tissue damage, a significant component of disease. Here we show in a mouse model of infection with pathogenic pandemic H1N1 (2009) influenza virus that an immunomodulatory drug, AAL-R, provides significantly greater protection than that occurring with the antiviral drug, oseltamivir. Combined administration of both AAL-R and oseltamivir enhances survival over that from either drug alone protecting 94% of infected mice from a lethal inoculation of virus. Mechanistically, AAL-R significantly downregulates host cellular as well as cytokine responses thereby limiting pulmonary damage ultimately enhancing survival without interfering with host control of pandemic H1N1 (2009) influenza virus replication. Suppressing cytokine storm using sphingosine analogs may prove to be a useful therapy against influenza virus as well as other respiratory diseases where immune-mediated tissue injury is a significant component of disease.
Defective CD8+ T cell effector function in pathogenic influenza infection (49.7)
Authors: Rutigliano John , Morris Melissa , Doherty Peter , Thomas Paul 
Published: January 2023

Abstract
Many questions about CD8+ T cell responses during influenza infection remain unanswered. We therefore examined the development and differentiation of CD8+ T cell memory populations based on specificity and effector function in a mouse model system comparing high and low pathological infections of influenza. Our findings reveal that initial or peak viral titer was not the determining factor in the outcome of disease. Instead, differences in CD8+ T cell effector function were observed for each virus type (high and low pathogenic), and these differences correlated with disease outcome. Further investigation has demonstrated that differences in the airway microenvironment after infection with high and low path infections may significantly affect CD8+ T cell activity. Specifically, increased early production of certain cytokines is associated with highly pathogenic infection. We hypothesize that this altered airway microenvironment results in downmodulation of CTL function via established negative feedback pathways.These phenotypic and functional analyses have revealed distinct effector memory CD8+ T cell populations in the context of influenza infection that have profoundly different capabilities for viral clearance.
Memory T cells generated in youth function well in old age (49.8)
Authors: Decman Vilma , Laidlaw Brian , Ertl Hildegund , Wherry E. John 
Published: January 2023

Abstract
Aging-associated changes negatively influence T cell responses. Since we previously observed that the memory CD8 T cells generated in aged mice have substantially reduced proliferative expansion upon secondary infection, we wanted to investigate if observed defects of memory T cells are due to the age of the cell or the age of the host when primed. Briefly, virus-specific memory T cells were generated by infecting young mice, aged mice or by infecting mice when they were young, but then allowing these mice to age for 2 years. T cells from these three groups were adoptively transferred to congenic young mice and these recipient mice were challenged to assess the recall capacity of memory T cells. We used both systemic (vaccinia virus or LCMV) and local (influenza virus) challenge models to investigate whether there were differences in the ability to respond to different types of infections and to assess the recall capacity of virus-specific T cells. Strikingly, the memory CD8 and CD4 T cells that were primed in young mice and then aged for 2 years responded as well as the memory T cells primed recently in young mice. These highly functional memory T cells appear largely impervious to age-associated changes occurring in their environment. As expected, memory CD8 and CD4 T cells recently generated in aged mice fail to mount strong recall responses. To conclude, our studies point to events during priming and the starting of T cell population in aged mice as a key area of focus.
TULA-family proteins are key to the regulation of T-cell-driven inflammatory response. (50.1)
Authors: Newman Tiffanny , Carpino Nicholas , Ganea Doina , Safadi Fayez , Tsygankov Alexander 
Published: January 2023

Abstract
The TULA-family consists of two proteins implicated in cellular regulation. TULA-1 is expressed in T-cells and is pro-apoptotic. TULA-2 is a ubiquitously expressed phosphatase that suppresses receptor-mediated signaling. T-cells from mice lacking TULA-1 and 2 (dKO) are hypersensitive to TCR stimulation. This may be due to these proteins having a similar function working synergistically or dissimilar functions having a convergent effect. To understand functional interaction of these proteins we have characterized TULA-family knockout mice without and during an immune challenge. We show that CD4+ T cells of dKO mice have an atypical CD45RB distribution, and that within this subset memory T-cells are expanded only in dKO not in single TULA knockouts. However, CD4+ T-cells of single knockout and wild-type mice respond differently to TCR stimulation as seen using signaling and responses in vitro. To evaluate consequences of TULA deficiency in vivo, we utilize two mouse models of inflammatory bowel disease: TNBS-induced colitis and colitis induced by the adoptive transfer of CD45RBHigh CD4+ T-cells. Studies utilizing TNBS indicate that deficiency of any TULA-family protein exacerbates TNBS-induced colitis. Likewise, dKO CD45RBHigh CD4+ T cells were significantly more colitogenic than cells from WT mice in the transfer model. Taken together, our data indicate that TULA-family proteins are key to the physiological regulation of T-cell reactivity that drives intestinal inflammation.
Disk large protein 1 promotes the initiation of isotype-switched IgG-BCR signaling (50.15)
Authors: Liu Wanli , Pierce Susan 
Published: January 2023

Abstract
B cell memory is critical for the protection from many infectious diseases and is the basis of many current vaccines. Memory B cells expressing high-affinity, IgG-BCRs give rise to the rapid production of high-affinity IgG antibody recall responses, the mechanisms by which the IgG BCRs function to enhance B cell responses are not understood. Studies in mouse models showed that the cytoplasmic tail of membrane-bound IgG (mIgG) is both required and sufficient for the enhanced IgG antibody recall response. Recently, we showed that the conserved membrane proximal region of the mIgG1 cytoplasmic tail, a region not previously appreciated to play a role in BCR signaling, was both necessary and sufficient to dramatically enhance the early events in the initiation of B cell activation. We now identify Dlg1 as a specific, antigen-induced binding partner of the mIgG1 cytoplasmic tail. We demonstrate that Dlg1 and mIg associate through a mechanism involving the binding of the N-terminal and PDZ domains of Dlg1 to the membrane proximal region of the mIgG1 tail. In response to antigens, Dlg1 is rapidly recruited to IgG1-BCR microcluster and then the IgG1-B cell immune synapse. Using live B cell imaging by fluorescence lifetime imaging microscopy we observed that antigen binding induces a molecular complex of Dlg1 and IgG-BCR. Our further evidence suggests that Dlg1 serves as a BCR adaptor stabilizing the formation of IgG-BCR oligomers and facilitating the assembly of signalosome.
Immunology and the liberal arts: constructing a multi-level immunology curriculum at an undergraduate institution (51.2)
Authors: Chatterjea Devavani 
Published: January 2023

Abstract
At a liberal arts college, immunology is not restricted to a specialized biology course. Its relevance to global public health attracts biology majors and non-majors. Its inherent evolutionary scaffolding and broad focus on cellular/molecular physiology makes it suitable for all levels of the majors’ curriculum. With sophisticated technology and model systems, and translational significance, it appeals to senior biology majors undertaking collaborative research with faculty, participating in journal club-style seminar courses and writing independent capstone papers. At Macalester College, we offer a multi-level immunology curriculum ranging from non-majors global and community health seminars on pandemics and vaccine development, an introductory immunology course, with laboratory and civic engagement components, for juniors, and senior-level seminar and research courses and honors research projects. Our flow cytometry core supports labs across the biology curriculum. With its inherent focus on integrative thinking and application of concepts to solving problems, relevance to global health and lastly, but importantly, room for concepts of identity, organization and collective action, immunology is a perfect liberal art. We present examples of course and laboratory innovations, strategies for funding a research laboratory at a liberal arts college, and ways of getting students across campus engaged in studying the immune system.
Toll-like Receptor 2 polymorphisms, signaling function and human disease (51.5)
Authors: Woodham Hadiya , Rees Steven , Medvedev Andrei 
Published: January 2023

Abstract
To introduce high school students to the molecular mechanisms governing health and disease, I recently developed a course entitled, “The Cell and Molecular Basis of Human Health and Disease”, which offers an exploration of how such fundamental processes as gene regulation, cell communication, and cell death form the basis of health and disease. To enhance the immunology unit within this course, I have developed a curriculum based on my summer research that is focused on current understanding of host antimicrobial innate defense and the impact of polymorphisms within Toll-like receptor (TLR) 2. Using transfection-based complementation of HEK293 cells, we found that R753Q inhibits TLR2-mediated activation of NF-kB and expression of IL-8 but does not affect TLR2 expression. Students will learn the basics of TLR innate defense, study TLR expression/functions and how expression of inflammatory cytokines is controlled by transcription
There’s no time to teach that: integrating the immune system, autoimmunity, literacy, and research into an over-crowded curriculum (51.7)
Authors: Pazol Jon 
Published: January 2023

Abstract
Because of various curricular mandates, teachers are faced with covering an ever-expanding range of topics with little room for study of more interesting aspects of biology. Adding to this problem is the need for many teachers to incorporate literacy strategies to remediate student deficits. In addition, assigning independent research often results in plagiarized reports based on unreliable sources. To manage these issues, I have developed a curriculum framework that utilizes autoimmunity, while simultaneously fostering increased literacy and improved research methods. After a general introduction to the immune system, students will explore the specifics of autoimmunity. Experimental Autoimmune Encephalomyelitis (EAE), the mouse model of Multiple Sclerosis currently being researched by Dr. Stephen D. Miller of Northwestern University, will be used as the basis. Students will read, summarize, and formulate questions about current immune-related news articles. Then they will engage in independent research about an autoimmune disease, utilizing relevant and appropriate web sites. Students’ website searches will not only focus on the disease, but will also require them to identify resources available for patients. Steering them in this direction will also provide them with a model for any type of future disease research. The unit is designed for flexibility in its implementation, and can successfully be transferred to a wide variety of topics.
Enabling in vivo visualization of cellular therapies in the clinic: generation of preclinical data sets (52.2)
Authors: Helfer Brooke , Balducci Anthony , Kalinski Pawel , Ahrens Eric , Wesa Amy 
Published: January 2023

Abstract
Cellular therapies are increasingly being used to modify a patient’s immune function in various areas of medicine, including cancer, infectious disease, and regenerative medicine. A question that remains with such therapies is the dispersion and persistence of cells after administration. Here we utilize a novel 19F MRI tracer agent to label Natural Killer cells (NK), T cells, dendritic cells (DC), and stem cells ex vivo and illustrate preclinical data sets which may be used to support a cellular therapeutic IND. Important therapeutic functions, such as differentiation of stem cells, migration and antigen processing of DC, and cytokine production and proliferation of NK and T cells, are maintained upon 19F labeling. Toxicity studies indicate that this 19F tracer lacks mutagenicity and, in acute toxicity studies, induces no adverse systemic or local effects at 100x the expected patient dose. In vivo results demonstrate the capability of MRI to detect and quantify labeled cells with a high degree of specificity. Since there is little exogenous fluorine present in tissue, labeled cells appear with little background. Pairing this signal with conventional proton MRI from the same imaging session, cells are able to be traced to their precise anatomical location. The MRI tracking capabilities, safety profiles, and use of 19F labeling in preclinical data sets demonstrate the ability of 19F to be used in clinical applications to strengthen the understanding of cellular therapeutics.
Longevity of memory CD8 T cell responses after multiple antigen-stimulations in vivo (52.26)
Authors: Badovinac Vladimir , Rai Deepa 
Published: January 2023

Abstract
Recently it has been shown that proliferative capacity and long term maintenance and survival of CD8 T cell responses (T-cell receptor transgenic - TCR-Tg) are controlled by the number of Ag-stimulations. Here, in a similar experimental design and using an adoptive transfer model we show that repetitive Ag-stimulation of endogenous memory CD8 T cells populations leads to the inability of those cells to undergo homeostatic proliferation and survive. In contrast, repetitive homologous boosting (up to 6 times) of memory CD8 T cells in situ (no adoptive transfer involved) did not lead to loss of memory CD8 T cells or their ability to survive, undergo homeostatic proliferation, and acquire a central memory (ie. CD62L high, CD27 high) phenotype and function (ie. IL-2 production). Interestingly, continuous boosting of Ag-specific CD8 T cells is required to preserve the numbers and increase the complexity of memory CD8 T cell responses. Thus, these results suggest that memory CD8 T cell responses in an individual host can survive multiple rounds of Ag-encounters and that repeated Ag-stimulation might be required for the host to sustain the quantity while maintaining the diversity (quality) of the memory CD8 T cell pool.
Activation of Wnt signaling preserves naive T cell phenotype (52.28)
Authors: Muralidharan Sujatha , Chakraborty Rikhia , Hanley Patrick , Bollard Catherine , Rodgers John , Savoldo Barbara , Dotti Gianpietro 
Published: January 2023

Abstract
The study of canonical Wnt-β catenin signaling in mature T cells in mouse models has shown that activation of Wnt signaling led to an arrest in effector T cell differentiation and promoted memory T cell formation. This project extends this investigation into human T cells and examines the effect of this signaling pathway on naïve-effector-memory development in mature human T cells. Recapitulating the results seen in mouse models may help to overcome limitations in clinical treatments such as adoptive T cell therapy for cancer since studies have shown that infusion of naïve or memory T cells improves in vivo persistence of these T cells. Wnt signaling was induced in polyclonally activated human T cells and after a week’s culture, there was a significant increase in naïve CD45RA+CD62L+ T cells (4 vs. 32%) and a corresponding decrease in effector CD45RO+ T cells (86 vs. 63%) as measured by flow cytometry. Cell expansion was significantly reduced as a result of an arrest in cell proliferation (88% vs. 27%). Treating Wnt-activated cells with IL-15, IL-7 or IL-2 restored proliferation but led to a corresponding loss of the naïve phenotype. Wnt signaling also led to impaired T cell effector function, in terms of degranulation (60 vs. 11%) and IFN-γ production (24% vs. 5%). Therefore, activation of Wnt signaling in mature human T cells preserves a subset of naïve T cells by arresting proliferation and impairs T cell effector function.
Qualitative and quantitative parameters predict functional humoral response to alum-adjuvanted immunization. (52.4)
Authors: Lynch Heather , Stewart Shelley , Riebe Kristina , Kepler Thomas , Alam S. , Sempowski Gregory 
Published: January 2023

Abstract
Adjuvants are crucial vaccine components for enhancing immune response to immunogens. Many potential adjuvant materials have been studied for their ability to augment the response to antigens while maintaining low toxicity. A US FDA approved adjuvant routinely used in humans is alum. The aim of this study was to comprehensively measure the ways in which innate immune signals induced by alum manifest in terms of the effect on the adaptive immune response to recombinant protective antigen (PA) from Bacillus anthracis. C57Bl/6 mice were given a single subcutaneous immunization with PA +/- alum at the base of each limb. Serum and draining lymph nodes were collected after immunization (days 1-70). On day 71, saline or PA only boost was administered, followed by additional serum and tissue collection (days 78-85). Using multi-color immunohistochemistry it was shown beginning day 10 that alum induces a rapid and strong germinal center response in the draining lymph node. This observation correlates with quantitative and qualitative changes in PA-specific antibody assessed by ELISA and Biacore (SPR). In addition, augmented antibody response to PA+alum resulted in increased antibody functionality, as determined by anthrax toxin neutralization assays. This study demonstrates a novel multi-parameter approach to evaluation of antigen-specific responses to immunization and the impact of adjuvants. This approach will be useful in the development and testing of novel adjuvants.