bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ran overexpression leads to a compromised transcription factor nuclear translocation and diminished T-cells response to TCR activation (35.8)
Authors: Pham Thi Ngoc Diep , Qiao Xiaoying , Valderrama-Carvajal Hector , Luo Hongyu , Wu Jianping 
Published: January 2023

Abstract
Ran (Ras-related nuclear protein) is a Ras family GTPase, and its documented functions are the regulation of DNA replication, cell cycle progression, nuclear structure formation, RNA processing and exportation, and nuclear protein importation. In this study, we performed detailed mapping of Ran expression during mouse ontogeny using in situ hybridization. High Ran expression was found various organs and tissues including the thymus cortex and spleen white pulp. Ran was induced in T cells 24 hours after their activation. Ran's function in the immune system was investigated. In transgenic T cells with actin promoter-driven Ran expression, there was compromised activation marker expression, lymphokine secretion, and proliferation upon T cell receptor (TCR) activation in vitro, compared with wild-type T cells. At the molecular level, transgenic T cells were defective in nuclear factor kappa-B (NFκB), activator protein 1 (AP-1) and nuclear factor of activated T cells (NFAT) nuclear translocation. Our experiments showed, for the first time, that Ran has important regulatory function in T-cell activation, and such function is probably related to its role in nuclear import of critical transcription factors.
The Regulation and Function of the TSLP Receptor in the Airway Epithelium (36.15)
Authors: Miazgowicz Michael , Headley Mark , Ziegler Steve 
Published: January 2023

Abstract
Epithelial cells of the airway and lung have been shown to participate actively in the response to both pathogenic and allergenic environmental stimuli. In particular, the airway epithelium is a potent source of thymic stromal lymphopoetin (TSLP), a cytokine that is strongly associated with asthma and other atopic pathogenesis. In the lung, TSLP acting in concert with an antigenic stimulus is capable of inducing hallmarks of the asthmatic response: eosinophilia and inflammatory cell infiltrates, sub-epithelial fibrosis, goblet cell hyperplasia and mucus production, airway hyperresponsiveness, and Th2 cytokine and chemokine production.
TSLP production by airway epithelial cells is known to be NF-κ B dependent. Surprisingly, we have found that factors known to upregulate TSLP is also capable of upregulating the heterodimeric TSLP receptor. Stimulation with either TNF-α or infection with Sendai virus results in the upregulation of both TSLPR and IL7R on a human airway epithelial cell line as well as primary murine airway epithelium. These same stimulatory conditions, in combination with the Th2 cytokine IL-4, furthermore result in the upregulation of TARC and CXCL5, chemokines associated with airway inflammation. Upregulation of these chemokines can be inhibited by the addition of an anti-TSLP monoclonal antibody, indicating a role for TSLP signaling in the expression of these genes by the airway epithelium.
Student use of learning resources to understand antimicrobial actions: use in hybrid vs on-line format (37.6)
Authors: Samuel Lysa , Muirhead Bill , Green-Johnson Julia M 
Published: January 2023

Abstract
Increased demand for online computer-based instructional resources has led to the need for effective utilization of learning objects in health biology courses. Our aim was to examine how well learning objects assist students in understanding challenging concepts in antimicrobial activity against infectious disease. Our specific focus was on learning object use in an introductory microbiology and immunology course in two different settings: a fully on-line section and a hybrid section, which integrates online materials with face-to-face lectures. To collect information on use of the learning objects, an anonymous survey was given to both sections. Survey participation rates varied, with a 56% rate from the online course, and only 28% from the hybrid course. Survey data analysis indicated many similarities between online and hybrid sections in learning object utilization, including high usage as study material for examinations. Differences were observed in the positive impact learning resources have on students learning difficult concepts, with the online course showing 100% agreement, and the hybrid course only 76% agreement, suggesting differences in learning object utilization for learning challenging new concepts. Qualitative responses provided further indications for effective learning object integration into differentiated instruction formats.
Funded by UOIT's Teaching Innovation Fund.
Active learning improves comprehension in large section immunology course (37.7)
Authors: Ersin Özlem H , Bandrick Meggan , Molitor Thomas W 
Published: January 2023

Abstract
Active learning eschews the traditional sage-on-stage model of education in favor of a collaborative learning environment where students share with faculty the responsibility for making learning happen. The approach is especially well suited for students in large lecture classes who might otherwise feel isolated, unengaged or reluctant to interact. At University of Minnesota, we use a variety of active learning techniques in our large section, upper level undergraduate immunology course. Active learning has allowed us to incorporate formative assessment as an ongoing aspect of our class, as well as to encourage active engagement of a wide base of students in discussions. We describe here an active learning module on the complement system and report on the relative efficacy of the approach in fostering student achievement. The complement system is a conceptually trying topic for the typical undergraduate student of immunology. Results of pre- and post-tests over three academic years indicate students in the active learning intervention score higher than those in the control group. However, despite superior knowledge gains, student satisfaction with the learning experience declines.
ENteric Immunity SImulator: A tool for in silico study of gut immunopathologies (166.15)
Authors: Wendelsdorf Katherine , Bassaganya-Riera Josep , Bisset Keith , Eubank Stephen , Hontecillas Raquel , Marathe Madhav 
Published: January 2023

Abstract
Here we present the newly developed ENteric Immunity SImulator (ENISI) that simulates the antagonistic inflammatory and regulatory immune pathways of the gut as individual immune cells interact with and respond to commensal and foreign bacteria. This tool has been used to reproduce a typical inflammatory response to foreign bacteria as well as the immunopathological effects of autoimmunity to commensal bacteria with 10^6 individual cells. ENISI is built on an agent-based model that incorporates spatial effects and randomness of cell-cell and cell-bacteria contact, which can have a significant impact on whether a triggered inflammatory cascade is successfully regulated or spirals out of control. Preliminary simulations indicate the importance of cell density and epithelial cell-mediated recruitment in determining gut immunopathology. In addition, such representation allows emergent properties such as changes in bacterial demographics and evolution as a result of interaction with host immune cells. This tool will be useful to i) test the plausibility of in vitro observed immune cell responses as explanations for tissue-level damage, ii) propose mechanisms not yet tested in vitro that could explain tissue-level phenomenon, iii) conduct low-cost, preliminary tests of proposed interventions/ treatments for inflammatory diseases, iv) identify specific data to be gathered experimentally in order to characterize mechanisms of immune modulation in the gut.
Modeling human rheumatoid arthritis in NHP: Type II collagen induced arthritis in cynomolgus macaques (167.4)
Authors: Zhang Kevin , Liu June , Deng Jilin , Chang Liangtang , Shao Jian , Lu Jun , Bendele Alison , Fu Yunfeng , Duan Jeff 
Published: January 2023

Abstract
Collagen induced arthritis (CIA) rodent models have been extensively used in rheumatoid arthritis (RA) research. An RA model in non-human primate (NHP) is particularly demanded because of the close phylogenesis that provides the cross-reactivity to human for different development compounds using most modern drug technologies. However, NHP RA model has been reported extremely difficult because of the low and inconsistent disease incidence. We studied type II collagen induced arthritis in Cynomolgus monkeys. Following immunization with collagen, the disease progression was monitored for 8 weeks. Overall the arthritic incidence reached 87% and the average arthritic incidence of proximal interphalangeal (PIP) joint reached near 90%, significantly higher than what was previously reported. The average swelling of PIP joint increased approximately by 45%. Radiography, histopathology and histomorphometry analysis of the joint bones well supported the arthritic disease with the similar characteristics of human RA joints. The average arthritic score was significantly reduced with the single agent treatment of Methotrexate or Dexamethasone. Our results demonstrated the successful establishment of an reliable CIA in Cynomolgus monkeys, providing a valuable tool for studies of RA disease in pathogenesis, biomarker, translational research, and most importantly, anti-arthritic therapeutics as well as other relevant diseases, such as anemia of chronic disease and arthritic pain.
Regulation of immunity during viral lung infection (168.1)
Authors: Loebbermann Jens , Thornton Hannah , Sparwasser Tim , Johansson Cecilia , Openshaw Peter 
Published: January 2023

Abstract
Regulatory T cells (Tregs) play a clear role in chronic infections and inflammatory disorders, but their role in acute infections have not been fully elucidated. Respiratory syncytial virus (RSV) is the major cause of serious lower respiratory tract infection in infants, resulting in over-exuberant immune responses. In order to examine the role of Tregs in primary RSV primary infection, we infected “Depletion of regulatory T cells” (DEREG) mice which express the diphteria toxin (DT) receptor enhanced GFP fusion protein under the control of FOXP3 gene locus. Injections of DT ablated Tregs, and depletion prior to RSV primary infection caused increased weight loss and increased influx of cells into the lung and the airways (bronchioalveolar lavage, BAL) with lung and BAL showing elevated numbers of CD4+ and CD8+ T cells on d4, d8 and d14 post RSV infection. Interestingly, Treg depletion also caused an increase in neutrophils and eosinophils in the airways. Therefore, Tregs do not only control the magnitude of the T cell response, but also the quality of the responses that follow. The effects of RSV infection in mice with defective immune regulation closely parallels the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation
The miR-17-92 cluster is essential for regulatory T cell function in vivo (168.14)
Authors: Jeker Lukas , De Kouchkovsky Dimitri , Esensten Jonathan , Bluestone Jeffrey 
Published: January 2023

Abstract
microRNAs (miRNAs) are posttranscriptional regulators of the proteome. We have identified CD28-responsive miRNAs in human CD4+ T cells. Among others, the miR-17-92 cluster was of particular interest because abnormal miR-17 levels have been reported in peripheral blood mononuclear cells from patients with multiple sclerosis. When activated with low CD28-costimulation the miR-17-92 cluster was necessary to drive maximal proliferation in conventional mouse CD4+ T cells (Tconv) in vitro. However, the miR-17-92 cluster was largely dispensable for total T cell numbers in secondary lymphoid tissues and for antigen-response in vivo. Since FoxP3+ regulatory T cells (Treg) are strongly co-stimulation dependent we deleted the miR-17-92 cluster specifically in Treg. Preliminary data suggest that as for Tconv the miR-17-92 cluster was dispensable for Treg numbers and function under homeostatic conditions, even in aging mice. By contrast, mice with miR-17-92-deficient Treg develop much more severe experimental autoimmune encephalitis than control mice. Preliminary results suggest that miR-17-92-deficient Treg numbers are significantly reduced in the spinal cord while antigen-specific effector cells are present in normal numbers. We are currently investigating how miR-17-92 mediates this crucial function. Our results demonstrate that miRNAs are critical for optimal T cell co-stimulation via CD28. The miR-17-92 cluster is essential for Treg function under inflammatory conditions in vivo.
Induction of adaptive regulatory T cells by HIV-infected dendritic cells is defective. (168.15)
Authors: Presicce Pietro , Rusie Laura , Moreno-Fernandez Maria , Fichtenbaum Carl , Chougnet Claire 
Published: January 2023

Abstract
Recent studies have shown that dendritic cells (DCs) can induce peripheral conversion of conventional T cells into regulatory T cells (Tregs). DCs are among the first targets of HIV and it is not known whether their infection or exposure to the virus alters their capacity to convert Treg. In our study, 10% of CD3+CD4+CD25-FOXP3- T cells (non-Tregs) expressed FOXP3 5 days after culture with autologous monocyte-derived DCs (moDCs). These converted FOXP3+ cells suppressed proliferation of responder T cells similarly to natural Tregs. In contrast, moDCs from HIV-infected patients were defective at inducing FOXP3 in autologous non-Tregs. MoDCs infected in vitro with a CCR5-using strain were also unable to induce FOXP3. Productive infection of the DC was not required, as DC exposure to inactivated HIV also impaired FOXP3 induction. This defect did not depend on IL-10 or TGF-β, as adding these cytokines did not restore FOXP3 induction. Higher T cell death was observed in infected cocultures than in uninfected ones. Our findings suggest that HIV-infected moDCs kill converted Tregs, leading to a poor induction of adaptive Tregs.
Adenosine signaling mediates the protective effects of regulatory T cells in kidney ischemia reperfusion injury (168.17)
Authors: Kinsey Gilbert , Huang Liping , Lobo Peter , Okusa Mark 
Published: January 2023

Abstract
Regulatory T cells (Tregs) suppress the innate inflammation and injury associated with kidney ischemia-reperfusion injury (IRI). Activation of adenosine 2A receptors (A2ARs) on immune cells also prevents renal injury after IR. Tregs express CD73, which is the rate-limiting enzyme in production of extracellular adenosine. We hypothesized that the production of adenosine by Tregs is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A2ARs on inflammatory cells. The ability of adoptively-transferred Tregs, isolated from WT and CD73KO mice, to protect WT mice from kidney IRI was compared in terms of renal function, tubular necrosis and kidney infiltrating leukocytes. WT Tregs protected WT mice from kidney IRI, but in the absence of adenosine generation (CD73KO) the functional capacity of Tregs to block kidney IRI was impaired (plasma creatinine 18hr post ischemia: Sham: 0.3±0.1*; IRI+non-Tregs: 1.4±0.3; IRI+WT Tregs: 0.4±0.1*; IRI+CD73KO Tregs: 1.0±0.3; *p&lt;0.05 vs. IRI+non-Tregs). WT Tregs offered significant, but incomplete, protection to A2ARKO mice. In contrast, WT Tregs completely protected A2BRKO mice, similar to WT mice. Taken together these findings suggest that adenosine production is vital for the protective effects of Tregs in IRI and suggest Treg-generated adenosine acts partially through A2ARs, in the recipient, to inhibit innate immune responses in kidney IRI.
Ex-vivo expanded DCs induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin allografts (169.12)
Authors: Kishimoto Hidehiro , Yamano Tomoyoshi , Suzuki Toshihiro , Abe Ryo 
Published: January 2023

Abstract
The principal function of Dendritic cells (DCs) is to promote T cell activation and differentiation into effecter T cells by presenting foreign Ags and providing costimulatory signals. Also DCs are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-MHC complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T cell development, induction of T cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs obtained from bone marrow cultured either with Flt3L (FLDC) or GM-CSF (GMDC) could induce allo-specific central and peripheral tolerance after i.v. injection; B cells were used as a control. The results showed that only FLDC reached the thymus after injection, and these cells induced both central and peripheral tolerance to donor MHC. For central tolerance, injection of FLDC induced antigen-specific negative selection of both CD8 and CD4 single-positive thymocytes. For peripheral tolerance, injection of FLDC induced donor-specific T cell unresponsiveness and prolonged survival of donor-derived skin grafts. Tolerance induction by adoptive transfer of Flt3L-induced DC could be a useful approach for promoting graft acceptance after organ transplantation.
Liver transplant tolerance: a new look at an old puzzle (169.17)
Authors: Ahearn Aaron , Klein Ingo , Lee Karim , Hayden Tracy , Liu Feng Chun , Tang Qizhi , Kang Sang-Mo 
Published: January 2023

Abstract
We explored the tolerogenicity of liver allografts (Ltx) by characterizing the phenotype and persistence of alloreactive T cells after spontaneously tolerant Ltx in mice. Using adoptive transfer of TCR-tg direct and indirect donor-reactive T cells, we found that LTx (BALB→B10) induced a stronger CD4 T cell response than either skin or heart Tx. Moreover, large numbers of donor-reactive T cells persist 21 days after Ltx and do not upregulate Foxp3, even though tolerance to subsequent allospecific skin grafts is established. In vivo MLR confirmed the persistence of endogenous effector CD4 T cells at 21 and 250 days post-Ltx. Overall, these findings are consistent with an ongoing effector alloresponse rather than immune regulation after Ltx. In contrast, the CD8 donor-reactive T cells were significantly reduced, though still detectable, after Ltx. However, post-Ltx animals selectively eliminate allogenic target cells in an in vivo CTL assay. Thus, deletion of effector CD8 T cells may help protect liver allografts, but cannot completely account for Ltx tolerance. Finally, CD4, CD8, and Total T cells isolated from day 90 post-Ltx mice reject donor skin grafts when transferred into Rag1-/- hosts, indicating that Ltx tolerance cannot be transferred via the immune compartment. These data demonstrate the magnitude and persistence of the anti-donor T cell responses after Ltx and opposes either deletional tolerance or regulatory T cell induction as mechanisms for Ltx tolerance.
Operationally tolerant kidney recipients exhibit higher numbers of suppressive CD19+CD24hiCD38hi b cells in relation to chronic rejection (169.25)
Authors: SILVA Hernandez , Takenaka Maisa , Vieira Pedro , Monteiro Sandra , Lemos Francine , Saitovitch David , Kalil Jorge , Coelho Veronica 
Published: January 2023

Abstract
Introduction: Immunotolerance in human transplantation remains a great challenge. The study of special individuals, called operationally tolerant (OT), that maintain stable graft functions after immunosuppression (IS) withdrawal can shed light into the field of transplantation tolerance. Objective: Investigate if OT involves a differential activation profile in the suppressive B cell population, CD19+CD24hiCD38hi (Bregs). Methods: We evaluated 5 OT, 10 Chronic rejection (CR), 19 stable graft function under standard IS (Sta) and 10 healthy (HI) individuals. We investigated the activation status of CD40/STAT3 signaling pathway in B cell subpopulations, analyzing STAT3 pTyr705 phosphorylation by flow cytometry. Results: We observed higher percentages in OT in relation to CR and STA (p&lt;0.05) and higher absolute numbers in both OT and HI in relation to CR (p&lt;0.05) of circulating Bregs. Despite the contrasting numbers of Bregs, the activation status of the CD40/STAT3 signaling pathway in these B cells was similar among all groups. Nevertheless, the fold of STAT3 phosphorylation increase (STAT3p+ cells post-stimulus/STAT3p+ cells pre-stimulus) was higher in OT than in CR (p&lt;0.05). Conclusions: Despite the normal suppressive B cell CD40/STAT3 pathway activation in all study groups, the significantly lower numbers and a less efficient functional mobilization of Bregs, in CR, suggest that the preservation of this population may be relevant to keep the state of operational tolerance.
Defective B cell memory and autoantibodies in subjects of cardiac transplantation in infancy (169.27)
Authors: Bender Diane , Schlater Amy , West Lori , Chinnock Richard , Platt Jeffrey , Cascalho Marilia 
Published: January 2023

Abstract
Aberrant functions of T cells and B cells may impair B cell memory and are thought to allow development of autoantibodies. Rarely, B cell memory defects and/or autoimmunity can be traced to specific mutations; however, in most cases which properties of T cells and B cells cause deficient B cell responses and/or autoimmunity are unclear. To answer these questions we studied child recipients of cardiac transplantation during infancy who, owing to removal of the thymus and T cell depletion at the time of surgery, have a greatly reduced T cell receptor repertoire diversity. We found these children to have impaired memory IgG antibody responses to polypeptide vaccines compared to controls, even though they appeared to mount IgM responses. These results suggest that the defective T cell compartment in recipients of cardiac transplantation in infancy impairs B cell memory and/or isotype class- switching. Remarkably, despite these defects and despite ongoing treatment with immunosuppressive drugs, 6 of the 9 subjects studied produced anti-ssDNA and rheumatoid factor antibodies as early as of 2 years of age. These findings suggest that the diversity of T cells and/or the availability of recent thymic emigrants are needed to generate B cell memory and prevent autoimmunity.
The role of antibodies in controlling reactivation of mCMV in immunocompromised bone marrow transplantation recipients (169.28)
Authors: Seefried Martina , Schneider Andrea , Mach Michael , Winkler Thomas 
Published: January 2023

Abstract
Reactivation of cytomegalovirus (CMV) is a frequent complication of bone marrow transplantation (BMT) and results in morbidity and mortality in immunocompromised recipients. In a previous study using murine CMV (mCMV) as a model, we have shown that transfer of memory B cells protects the immunodeficient host from the lethal course of mCMV infection. Here we demonstrate the impact of antibodies on the reactivation of mCMV in a murine model of BMT. We find that previous depletion of B cells (anti-CD20 antibody) during primary mCMV infection results in a profound reactivation of mCMV after syngeneic BMT. Our data show a negative correlation between virus-specific serum IgG titer and reactivation of mCMV after BMT. Therefore, our studies suggest that antibodies play a major role in controlling recurrent mCMV infection after BMT.