bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased type I interferon disrupts marginal zone barrier integrity via dissociation of lymphotoxin-expressing B cells and marginal zone macrophages in systemic autoimmunity (P4160)
Authors: Li Hao , Wu Qi , Yang PingAr , Li Jun , Fu YangXin , Mountz John , Hsu Hui-Chen 
Published: January 2023

Abstract
In the spleen, membrane expressed Lymphotoxin (LT) on B cells maintains the integrity of marginal zone macrophages (MZM) which acts as the final barrier to prevent follicular entry of autoantigens derived from apoptotic debris. In this study, we found that there was an age-dependent decrease in the number of MZMs and clearance of apoptotic debris in the spleens of autoimmune BXD2 mice. Selective depletion of MZMs by repeated injection of recombinant LTR fusion protein to BXD2 mice accelerated autoimmune phenotypes. Interestingly, in BXD2 spleen, the major LT producing MZ and MZ precursor B cells are primarily localized in the follicles due to type I IFN-induced upregulation of CD69. Adoptive transfer of B cells from BXD2-Ifnar-/- but not BXD2 to BXD2-Rag2-/- mice resulted in retention of B cells in the MZ, leading to repopulation of MZMs. Consistent with this, there was no age-related loss of MZMs in the spleens of BXD2-Ifnar-/- mice. Reconstitution of BXD2-Rag2-/- with a mixed bone marrow of BXD2-GFP+Ifnar+ and BXD2-GFP-Ifnar- (1:1) resulted in a 50:50 repopulation of donor MZMs in recipient mice, thereby excluding the direct effect of type I IFNs on MZM maintenance. Our present study suggests that one novel mechanism associated with type I IFN-induced autoimmunity is related to the effects on promoting follicular migration of LT expressing B cells. The dissociation of LT+ B cells and MZMs disrupts MZ barrier and enables follicular entry of apoptotic antigens.
Differential efficacy of human mesenchymal stem cells on disease in murine lupus based on source of origin. (P4162)
Authors: Collins Erin , Gu Fei , Naga Osama , Gilkeson Gary 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that targets multiple organ systems. A population of non-hematopoetic stem cells, mesenchymal stem cells (MSC), are of increasing interest as a therapeutic option for autoimmune diseases such as SLE. MSCs can be derived from various sources such as bone marrow or umbilical cords. In this study we examine the efficacy of human MSCs with varying origin on disease in murine based lupus. Human MSCs were harvested from umbilical cords, healthy donor bone marrow, and lupus patient bone marrow. We showed that in MRL/lpr mice, MSCs from all sources improved survival, increased body weight, and decreased proteinuria. Glomerular IgG, but not C3, deposition is significantly decreased in mice receiving umbilical cord and healthy donor MSCs. However, MSC from lupus patients caused a significant increase in glomerular C3 and IgG. Although no differences were seen in the percentage of CD4+ or CD8+ T, mice receiving lupus MSCs experienced a 2-fold increase in the percentage of Foxp3+ cells in the spleen. These mice also experienced this percentage increase in TCRβ+, B220+, and CD138+ cells in the bone marrow. Human MSC from various origins all made an impact on the disease severity of lupus prone mice. However, these results suggest that MSCs from healthy donors or umbilical cords appear to be more effective in murine lupus than the MSCs derived from lupus patients.
Dysfunction of hepatitis B virus-specific CD8 T cells depends on viral load and is partially regulated by PD-1:PD-L1 interaction in a mouse model of persistent infection (P6123)
Authors: Chen Chih-Yeh , Chou Ho-Yuan , Huang Ya-Hui , Tao Mi-Hua 
Published: January 2023

Abstract
The levels of functional impairment of CD8 T cells in chronic hepatitis B patients are correlated with viral loads, where the mechanisms underlying this dysfunction remain unclear. Taking advantage of a mouse model of chronic HBV infection mediated by adeno-associated viral vectors carrying HBV genome (AAV/HBV), we demonstrated that the function of HBV-specific CD8 T cells lost gradually during persistent infection with high viral load of AAV/HBV and was irreversible with therapeutic vaccination, while infection with low viral load resulted in a less extent of functional impairment, which was restored after vaccination. Consistently, CD8 T cells expressed increasing levels of inhibitory receptors in a viral load-dependent manner, especially programmed death 1 (PD-1). Furthermore, in PD-L1 KO mice infected with AAV/HBV, the levels of viral antigen decreased, concomitant with more potent function of specific CD8 T cells. However, the reduction maintained only in KO mice with low viral load, whereas the antigen levels rebounded in those infected with high load, suggesting the roles of other factors beyond PD-1:PD-L1 signaling pathway in regulating immune tolerance in chronic hepatitis B infection. Collectively, our data indicate that the viral load-dependent dysfunction of CD8 T cells induced in chronic HBV infection is partially regulated by inhibitory signal via PD-1, and blocking PD-1:PD-L1 alone may not be sufficient to rescue the immunity against persistent HBV infection.
Splenic natural killer cells act early to select viral escape mutants during murine cytomegalovirus infection (P6135)
Authors: Parikh Bijal , Han Patricia , Rivenbark Joshua , Yokoyama Wayne 
Published: January 2023

Abstract
The large double-stranded DNA genome of murine cytomegalovirus (MCMV) is stable both in vitro and in vivo in the absence of immune pressure. However, one month after inoculation of plaque-purified MCMV into T cell-deficient mice, viral clones emerge with mutations in the viral MHC class I-like molecule, m157, due to selection by natural killer (NK) cells. While the emergence of escape mutants is dependent on the cognate interaction of m157 with the Ly49H NK cell activation receptor, the mechanism for mutant virus selection has not been fully dissected. Surprisingly, we show here that diverse mutations were already present in the salivary glands of C57BL/6 mice 14 days post-infection, much earlier than previously reported. Upon re-inoculation, MCMV was then subjected to purifying selection with one dominant clone emerging. To address the role of NK cells and the specific organs involved, we designed a single nucleotide polymorphism genotyping assay to quantify selection for a mutant virus with a single point mutation in m157 during a mixed infection. Remarkably, our results suggest that the escape mutant was initially selected in the spleen, but not the liver, as early as 2 days post-infection. Together, these findings suggest that the selective pressure exerted by NK cells on MCMV occurs primarily in the spleen during the initial rounds of viral replication, indicating that the host innate immune system exerts pressure on the virus almost immediately upon infection.
Commensal bacteria and T cells control the generation of memory NK cells (P6103)
Authors: Kamimura Yosuke , Lanier Lewis 
Published: January 2023

Abstract
Previously, only T and B cells were thought able to generate long-lived memory cells; however, recent studies demonstrated that natural killer (NK) cells expressing the activating Ly49H receptor undergo clonal expansion, contraction, and generate long-lived memory cells after infection with mouse cytomegalovirus (MCMV). It is still unclear which subsets of NK cells preferentially give rise to memory NK cells. In this study, we show that expression of killer cell lectin-like receptor G1 (KLRG1) defines short-lived effector cells and precursor for long-lived memory cells. We found that sorted KLRG1-, but not KLRG1+ NK cells can generate memory cells. Interestingly, the percentage of KLRG1+ NK cells is significantly increased in Rag1-/- mice and Rag1-/- NK cells are largely impaired in the generation of memory cells. This phenotype was rescued by mixed bone marrow chimeric (wild-type:Rag1-/-) mice. Notably, the same results were also demonstrated in Tcra-/- or T cell-depleted mice. Meanwhile, the percentage of KLRG1+ NK cells was decreased in germ-free mice and antibiotic treatment enhanced memory generation. We further determined that steady-state cytokines induced by nucleotide-binding, oligomerization domain-containing protein (Nod) 1 and Nod2, but not Myd88 and Trif are responsible for the induction of KLRG1+ NK cells. Taken together, our findings demonstrate that commensal bacteria and T cells reciprocally regulate the generation of long-lived memory NK cells.
ZBTB20 is an adjuvant-specific regulator of long-term antibody responses (P1439)
Authors: Wang Yinan , Bhattacharya Deepta 
Published: January 2023

Abstract
The duration of antibody production following immunization can vary greatly depending on the vaccine, but the molecular basis for these differences is unknown. Here, we demonstrated that ZBTB20 is an adjuvant-specific transcription factor critical for the durable antibody production by long-lived plasma cells. ZBTB20 was highly expressed in germinal center and memory B cells and in short and long-lived plasma cells, but not in naïve B cells.Zbtb20 deficiency due to a gene trap mutation in the Zbtb20 locus specifically led to defective accumulation of long-lived plasma cells following immunization, while short-lived plasmablasts and germinal center B cells were unaffected. Competitive fetal liver reconstitution experiments demonstrated a B cell-intrinsic requirement for ZBTB20 in long-term antibody production following alum-adjuvanted immunization. Strikingly, inclusion of Toll-like receptor ligands in the adjuvant completely rescued long-term antibody production in Zbtb20-deficient fetal liver chimeras. Thus, different immunization conditions induce long-lived plasma cells with qualitatively distinct transcriptional programs to regulate their turn-over.
Children diagnosed with common variable immune deficiency show distinct T cell maturation phenotypes when compared with adults (P3333)
Authors: Issa-El-Khoury Karine , McCusker Christine , Mazer Bruce , Alizadehfar Reza , Ben-Shoshan Moshe 
Published: January 2023

Abstract
INTRODUCTION: Common variable immune deficiency (CVID) is considered primarily a B cell disorder characterized by low immunoglobulin levels, defective specific antibody production and susceptibility to sinopulmonary infections. Recent studies have implicated T cells in the pathogenesis of CVID. OBJECTIVES: To compare T cell maturation in children and adults with CVID. METHODS: Through PRIMES (Canadian Primary IMmunodeficiency Evaluation Study) registry, we recruited eight children and ten adults with CVID. T cell phenotype was assessed by flow cytometry. Patients were compared to healthy controls (thirteen children and ten adults). Wilcoxon Rank Sum test was used to assess differences in T cell subsets. RESULTS: Total lymphocyte count, CD3, CD4 and CD8 lymphocytes were decreased in children with CVID compared to controls (p=0.0006, p=0.0003, p=0.0003, p=0.03). Percentage and absolute numbers of naïve (p=0.012, p=0.002) and absolute numbers of memory cells (p=0.001) were decreased in children with CVID. However, there were no statistical differences between adults with CVID and healthy controls. DISCUSSION: Our data shows decreased T cell subsets in childhood CVID while levels in adults were normal. Studies assessing temporal trends in T cell subsets are required to determine if these differences in children are due to age-related compensatory mechanisms or if different mechanisms play a role in the pathogenesis of childhood versus adult onset CVID.
Shared epitope impacts arthritis by influencing CD4 T cell differentiation (P3321)
Authors: Luckey David , Behrens Marshall , Luthra Harvinder , David Chella , Taneja Veena 
Published: January 2023

Abstract
HLA-DRB1*0401 has been associated with predisposition to develop rheumatoid arthritis (RA) while *0402 has been linked with resistance to develop RA. Using transgenic mice, we showed that *0401 mice are susceptible to develop collagen-induced arthritis (CIA) that mimics human disease in histopathology, production of autoantibodies and sex-bias while *0402 mice are not susceptible. In this study, we determined if *0401 mice have CD4 T cell repertoire that is predetermined to produce proinflammatory cytokines. The data shown here supports that both *0401 and *0402 mice can produce Th1/TH17 cytokines although conditions required for production of Th17 cytokines differ between the 2 strains. In context of CIA, *0402 mice generate a Th2 response that may explain its resistance to develop CIA. Further, our data supports that a significant subset of naïve CD4 T cells when activated in polarizing conditions can generate T regulatory cells in *0402 but not *0401 mice. We hypothesize that *0401 has been evolutionarily selected due to its ability to clear infection. Our data suggests that *0401 generates a storm of cytokines in response to bacterial products and may be more efficient in clearing infection than *0402. Autoimmunity is a bystander effect of the cytokine storm ensuing immune dysregulation along with the presence of lower number of T regulatory cells in *0401 mice.
Engaging students in immunology via easy, low risk, active learning exercises (P4525)
Authors: Lukin Kara 
Published: January 2023

Abstract
Apathy toward science in high school and college students has reached alarming proportions. The lack of scientific understanding and basic knowledge of biology is creating both health and economic crises in the United States. Traditionally, college science courses have been completely lecture-based. However, lecture-free teaching and active learning strategies engage students more successfully in the content and help students solidify content knowledge more effectively. Students also find these educational formats more enjoyable than lectures. Here, several low risk activities which force students to prepare content prior to its explanation in class are presented. In particular, the use of immediate-feedback assessment tool cards and student-led lectures in teaching immunology are detailed.
Discovering optimal targets for adoptive T-cell immunotherapy of leukemia (P4346)
Authors: Vincent Krystel , Hadj-Mimoune Sarah , Hardy Marie-Pierre , Perreault Claude 
Published: January 2023

Abstract
The main barrier in allogeneic hematopoietic cell transplantation is the risk of developing graft-versus-host disease. This can be prevented by the injection of CD8 T cells targeted to leukemia associated antigens (LAAs) or minor histocompatibility antigens (MiHAs). Several studies in humans have established the value of LAAs and MiHAs as target for immunotherapy on solid tumors and leukemia, respectively. Importantly, their therapeutic efficacy has never been assessed on a per antigen basis. Thus, our goal is to directly compare the therapeutic efficacy of T-cells targeted to LAAs or MiHAs expressed on EL4 cells. We selected 4 MiHAs and 4 LAAs and confirmed their immunogenicity by in vitro cytotoxicity assays. We evaluated the anti-leukemic activity of antigen-specific CD8 T cells in vivo. Notably, mice immunized against MiHAs showed enhanced survival compared to mice immunized against LAAs. We found that decreased survival of EL4 bearing mice cannot be explained by weaker MHC I/Peptide interactions. Interestingly, we showed that T cells specific for 4 LAAs and 1 MiHA are undetectable by flow cytometry and that the abundance of tetramer positive cells correlates strongly with survival of EL4 bearing mice. We propose that CD8 T cells, mainly targeted to LAAs, bind weakly to their MHC I/Peptide complexes, leading to decreased immunogenicity. We believe that the insights gained from our studies will serve as guide for selecting the best antigens for future clinical trials.
Immunomodulation through CD40 and TLR-4: an approach to control tuberculosis (P4516)
Authors: Khan Nargis , Agrewala Javed 
Published: January 2023

Abstract
The immune system have nature's one of the most fascinating mechanisms which continuously protects us against billions of pathogens. It operates through a very well organized network of cells that constantly rove, communicate and coordinate to protect the host. The cells of the immune system regulate through sequence of events involving myriad of molecules expressed on their surface (costimulatory molecules, toll-like receptors, etc.) and also by soluble mediators (cytokines, chemokines, defensins, complement components, etc.). Moreover, the intricate interaction of these molecules among different immune cells like T cells, B cells, dendritic cells (DCs), macrophages, etc., elicit their activation or inhibition, thereby conferring resistance against various pathogens and maintain homeostasis of the immune system. Signaling of these molecules that are expressed on the surface of immune cells can further enhance their efficacy in elimination of pathogens. The study conducted by us showed that concomitant signaling through CD40 and Toll-Like Receptor-4 augmented the production of nitric oxide and proinflammatory cytokines like IL-6, TNFa and IL-12 in Mycobacterium tuberculosis (Mtb) infected DCs. Further, activated DCs showed enhanced microbicidal function and significantly reduced the intracellular survival of Mtb. This study indicates that concomitant signaling through CD40 and TLR-4 can be employed as a therapeutic strategy to curb the intracellular growth of pathogens.
Highly immunostimulatory RNA derived from a SeV defective interfering viral genome. (P4522)
Authors: Lopez Carolina , Mercado Xiomara 
Published: January 2023

Abstract
Defective interfering viral genomes (DIVGs) are generated during RNA viral replication. They are strong inducers of dendritic cell maturation and cellular immune responses. Virus stocks rich in DIVGs induce the expression of high levels of IFN-β, IL-12, IL-6 and other cytokines in cell cultures. Previous studies suggest that DIVGs induce cytokine expression through the action of cell pattern recognition receptors, specifically the members of the RIG-I like receptors. Whether DIVG recognition by these viral sensors and the resulting high cytokine expression depends on the DIVG sequence, structure, or length has not been addressed. In vitro transcribed RNA of Sendai virus DIVGs of different lengths and compositions were generated and tested for their stimulatory ability. Our results suggest that DIVGs specific structures and sequences are essential for their ability to trigger high cytokine expression thought RIG-I like receptor recognition. Moreover, we have generated a shorter DIVG with the identified minimal stimulatory motif that induce higher levels of IFN-β expression in vitro. In order to determine its immunostimulatory potential in vivo, we injected mice with DIVG RNA. Higher expression of pro-inflammatory cytokines was detected in the footpad tissue as early as 6 hours post-injection. This SeV-derived oligonucleotide with strong immunostimulatory activity may be then harnessed as a potent adjuvant for vaccination.
Temporal requirement for B cells in CD4 T cell responses (P4523)
Authors: Mollo Sarah , Harrington Laurie 
Published: January 2023

Abstract
B cell depletion therapy is used to treat patients with non-Hodgkin’s lymphoma and autoimmune diseases, yet how a reduction in the B cell population effects the development and maintenance of memory CD4 T cells is not fully understood. Infection models using B cell-deficient mice suggest B cells play a critical role in CD4 memory T cell development; however, it has been difficult to ascertain whether this effect is due to disrupted lymphoid architecture or a direct requirement for B cells during infection. Initial experiments demonstrate that MHCII on B cells is required for optimal CD4 T cell responses to Listeria monocytogenes (LM) infection, suggesting that B cells are essential for antigen-presentation to CD4 T cells. In order to determine the temporal requirements for B cells in the development and maintenance of memory CD4 T cells, wild-type mice were treated with anti-CD20 at different stages during LM infection. B cells are not required during the contraction and/or maintenance phases for LM-specific CD4 T cell memory responses; however, when B cells are depleted prior to CD4 T cell priming there is a reduced frequency and number of LM-specific effector and memory CD4 T cells capable of producing IFNγ and IL-2. Additionally, B cells are required for recall responses after the formation of memory CD4 T cells. These studies suggest an indispensable role for B cells in the generation of memory CD4 T cells and the initiation of robust secondary responses during infection.
A novel programmed death 1 isoform-based fusion DNA vaccine enhances functional antigen-specific CD8+ T cell immunity (P4499)
Authors: Cheung Allen , Zhou Jingying , Liu Henggui , Tan Zhiwu , Chen Zhiwei 
Published: January 2023

Abstract
Inducing an effective CD8+ T cell immunity is important in the protection and elimination of infectious pathogens. Programmed death-1 (PD1) up-regulation in in chronic infections (e.g. HIV-1 and TB) results in “exhausted” function of CD8+ T cells, but is restored by blockade of the PD1/PD-L pathway with antibodies or a soluble form of (s)PD1. Apart from sPD1, the other three spliced variants previously identified currently have no known function. In this study, we identified a new isoform of human PD1 that contains a 42-nucleotide in-frame deletion located at exon 2 near its IgV domain found expressed in PBMCs, named Δ42PD1. We found that Δ42PD1 is distinct from PD1 as it does not engage PD-L1 or PD-L2 and capable of inducing the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Next, we used Δ42PD1 as an intramolecular adjuvant to construct a DNA fusion vaccine with HIV-1 Gag p24 antigen. Following immunization in Balb/c mice, a significantly enhanced level of anti-p24 antibody titer and p24-specific CD8+ T cell responses were elicited that persisted for at least 7.5 months. Furthermore, vaccinated mice were protected against pathogenic vaccinia-Gag virus challenge, likely due to the improved proliferative and cytotoxic functions of the elicited CD8+ T cells. Therefore, our study demonstrates that a novel Δ42PD1 variant that amplifies the generation of antigen-specific CD8+ T cell immunity when used in a DNA vaccine.
Two HLA-A*0201-restricted epitopes identified from herpes glycoprotein B are recognized exclusively by CD8+ T cells from asymptomatic individuals and protect against ocular herpes (P4517)
Authors: BenMohamed Lbachir , Dervillez Xavier , Qureshi Huma , Chentoufi Aziz , Diaz Oscar , Sidney John , Villacres Maria , Wechsler Steven , Sette Alessandro , Nesburn Anthony 
Published: January 2023

Abstract
Identification of human “asymptomatic” HSV-1 epitopes that induce CD8+ T cells would help in designing an immunotherapeutic vaccine against herpes. Here, the HSV-1 gB sequence was screened for potential HLA-A*0201 CD8+ T cell epitopes using a variety of algorithms. The ability of these epitopes to induce multi-functional CD8+ T cell responses was compared in 10 “symptomatic” vs. 10 “asymptomatic” individuals. Ten potential epitope peptides were tested for affinity to HLA-A*0201. gB441-449 and gB561-569 exhibited high affinity to, and significantly stabilized, HLA-A*0201 molecules on the surface of T2 cells. Peptide-specific CD8+ T cell proliferation (CFSE dilution) and CD107a/b cytotoxic degranulation against these two epitopes was found in all 10 “asymptomatic” individuals. Recognition by “asymptomatic” CD8+ T cells was validated for the two epitopes using HLA/peptide tetramers. Staining for IFN-γ, IL-2, and TNF-α revealed dual- and triple-positive CD8+ T cells, indicating that these gB peptide-specific CD8+ T cells were (poly)functional. The CD8+ T cell responses to these two epitopes were absent in “symptomatic” individuals. A lipopeptide/rAdv5 prime/boost mucosal vaccine using these asymptomatic CD8+ epitopes induced strong, long lasting CD8+ T-cell protective immunity against ocular herpes in susceptible HLA-A*0201 “humanized” transgenic mice. The HSV-gB-epitope repertoire for human CD8+ T cells is more restricted than previously suspected.