bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a conserved self-antigen bearing the 2F5 neutralizing epitope of the HIV-1 gp41 Membrane Proximal External Region (105.2)
Authors: Yang Guang , Holl T. , Liu Yang , Li Yi , Lu Xiaozhi , Nicely Nathan , Kepler Thomas , Alam S. , Liao Hua-xin , Spicer Leonard , Haynes Barton , Kelsoe Garnett 
Published: January 2023

Abstract
Accumulating evidence suggests that the efficient generation of neutralizing HIV-1 antibody may be proscribed by immunological tolerance. The majority of monoclonal human antibodies, including 2F5, that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian cells. Introduction and expression of the 2F5 VDJ rearrangement in knock-in mice results in a B-cell developmental blockade that is characteristic of immunological tolerance. If immunological tolerance does prevent regular expression of neutralizing 2F5-like antibody, then discrete autoantigens that structurally mimic the HIV-1 2F5 epitope are present in mammals. Here, we demonstrate that the 2F5 antibody precipitates a small number of proteins from mouse and human cells, including a major component with a molecular mass of about 50 kDa. We have identified this 50 kDa protein as kynureninase (KYNU), a conserved component of tryptophan metabolism. Remarkably, the conserved H3 domain of mammalian KYNU contains the core 2F5 epitope (ELDKWA), and mutation within this region greatly diminishes 2F5 binding. The 2F5 antibody and its inferred, unmutated precursor bind KYNU with high affinity and specificity. Indeed, recombinant human KYNU is an effective inhibitor of 2F5 binding to HIV-1 envelope. The nature of KYNU as autoantigen was previously unknown and our study suggests that mimicry of self-antigens may represent a general evolutionary strategy of viral pathogens.
Anti-Ebola GP monoclonal antibodies protect mice and guinea pigs against lethal ebola virus challenge (105.29)
Authors: Qiu Xiangguo , Lisa Fernando , Alimonti Judie , Feldmann Heinz , Kobinger Gary , Jones Steven 
Published: January 2023

Abstract
Introduction: Ebola virus (EBOV) causes acute hemorrhagic fever in humans and nonhuman primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (mAbs) against Ebola glycoprotein in a mouse and guinea pig model. Methods: Healthy mice or guinea pigs were given mAbs i.p. in various doses individually or as pools of 3-4 mAbs to test their protection against a lethal dose of mouse- or guinea pig-adapted EBOV. Results: Each of the 8 mAbs (100 microgram) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven mAbs were effective 2 days post-challenge (dpc), with 1 mAb demonstrating partial protection 3 dpc. Furthermore, 4 mAbs achieved 70-100% protection with a single dose of 12.5 microgram at 1 dpc. In the guinea pig model each mAb showed partial protection 1 dpc, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 mAbs completely protected the majority of animals, while administration 2-3 dpc achieved 50-100% protection. Conclusions: Our data suggests the mAbs generated are capable of protecting both animal models against a lethal challenge of Ebola virus. These results indicate that mAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.
HIV Env-mediated, CCR5-dependent depletion of human Vgamma2Vdelta2 T cells (105.33)
Authors: Li Haishan , Mei Bing , Pauza C. David 
Published: January 2023

Abstract
Human Vgamma2Vdeta2 T cells are depleted during HIV infection. The majority of cells in this population are CD4-negative and do not support productive HIV infection; the mechanism for depleting them remains unknown. We noted recently that macaques immunized with an HIV R5-tropic gp120, also experienced severe Vgamma2Vdelta2 T cell depletion. A subsequent in vitro study showed that several different R5-tropic gp120, including those from Bal, ADA, YU2 and CN54 strains, induced human Vgamma2Vdelta2 T cell death that was inhibited by a CCR5 binding antagonist (Maraviroc) and a Caspase 8 inhibitor. The Vgamma2Vdelta2 may be especially vulnerable to cell death because they express high levels of CCR5 that could be modulated by Rapamycin treatment with a consequent reduction in Env-mediated cell killing. We have observed R5-tropic gp120 induced Vgamma2Vdelta2 T cell depletion both in vivo and in vitro, which was mediated by CCR5 receptor and Caspase 8 signaling pathway. We have identified a potential mechanism for Vgamma2Vdelta2 T cell depletion in HIV disease.
Immunogenicity of novel consensus-based DNA vaccines against Hepatitis B core Antigen. (106.1)
Authors: Obeng-Adjei Nyamekye , Yan Jian , Choo Daniel , Weiner David 
Published: January 2023

Abstract
Although effective vaccine against hepatitis B virus (HBV) has existed for over 3 decades, it still continues to be a major epidemic, especially among people of Asian and African descent. There are about 370 million people chronically infected and at risk of developing liver cirrhosis and liver cancer. The only therapies available for chronic infected individuals are interferon-α and nucleoside, which unfortunately do not control viral replication in most patients. This failure in protection with current HBV vaccines in 15% of individuals and the difference in response to treatment in the chronic infected are due, but not limited, to the genetic divergence among different HBV genotypes and to the immune escape mutations that often occur within the surface antigen (HBsAg). To circumvent these issues, we propose a novel consensus-based approach to vaccine design for HBV, using DNA vaccine strategy. A plasmid was designed based on HBV core (HBcAg)-specific consensus sequence from (which genotypes of HBV) with modifications such as codon and RNA optimization for maximum expression. We show that the construct was able to induce a strong antigen-specific T cell response systematically and in the liver of C57BL/6 mice. In addition, a high titer antibody response capable of recognizing a native HBcAg was observed in mice systematically immunized with this construct.
Adjuvanting influenza virus-like particles with glycophosphatidylinosital-anchored immunostimulatory molecules by protein transfer to enhance antiviral immune responses (106.14)
Authors: Patel Jaina , Song Jae Min , Shashidharamurthy Rangaiah , Compans Richard , Kang Sang-Moo , Selvaraj Periasamy 
Published: January 2023

Abstract
The effortless nature through which influenza, a bilayered lipid enveloped virus, can spread via an aerosol route and cause mortality is distressing. The use of virus-like particles (VLPs), that consist of a virus’ capsid proteins but not the viral genome required for replication, as vaccine candidates proves beneficial due to their safe nature and structural similarity with the live virus. In this study, we show that the incorporation of GPI-anchored immunostimulatory molecules onto H5 influenza VLPs can be accomplished through a quick, easy and stable protein transfer method. Affinity chromatography was used to purify the GPI-proteins (ICAM-1 and IL-12) from CHO-K1 cell lysates and incorporation onto the VLPs was determined by western blot analysis. To verify that incorporation occurred specifically via the GPI-anchor, PI-PLC treatment before and after incorporation and inhibition by fatty-acid binding proteins was carried out. Finally, electron microscopy was used to determine whether the structural integrity of the VLPs was altered following protein transfer. Our results indicate that incorporation of both GPI-proteins onto influenza H5 VLPs occurred following a 2 hour incubation at 37°C without disturbing the structural integrity of the VLPs. Therefore, this protein transfer method can be used to enhance the immunogenicity of VLPs easily and quickly to then be used as a potential influenza vaccine.
Therapeutic potential of zoledronic acid in enhancing immune function in aged mice (106.3)
Authors: Ventevogel Melissa , Riebe Kristina , Barefoot Brice , Ramsburg Elizabeth , Sempowski Gregory 
Published: January 2023

Abstract
Hematopoietic stem cells originate in the bone marrow and give rise to immune cells. Zoledronic acid (ZA) is a bisphosphonate shown to modulate skeletal and immune systems. Hip fracture patients treated with ZA had a significant increase in bone density and increased longevity over placebo. We hypothesize ZA treatment will promote bone density in aged mice which in turn will enhance immunity. Young/aged mice were treated with saline or ZA (IV 100ug/kg) and euthanized at 1, 3 and 6 months to determine the impact of ZA on immune homeostasis. Compared to control, ZA-treated young mice showed significant improvement in bone volume. ZA-treated aged mice showed a qualitative improvement in bone volume. Frequency of DN thymocytes and sjTREC were increased over control in ZA-treated aged mice, suggesting improved thymopoiesis. Potential of ZA for improving immunity was also explored. Mice were treated with ZA (3 mo), immunized with flu HA protein (IN, d0,7,14) and then challenged with PR8 influenza (d42). HA-specific Ab response and survival was assessed. No difference in response was observed with ZA treatment in young mice. ZA-treated aged mice however had a stronger HA-specific response over control, suggesting ZA enhanced host response to immunization. Survival of ZA-treated aged mice was also higher than control, suggesting a single infusion of ZA enhances immunity. Given these data, further investigation of ZA as a potential therapeutic for immune senescence is warranted.
Expression of ligands for the NKG2D activating receptor are linked to proliferative signals (108.2)
Authors: Jung Heiyoun , Raulet David 
Published: January 2023

Abstract
NKG2D is an activating receptor expressed on NK cells, CD8 T cells, and portions of NKT cells, gd T cells and CD4 T cells. The ligands for NKG2D receptor are surprisingly diverse, and emerging evidence suggests that different ligands are regulated by distinct cellular stress pathways, and in some cases a specific ligand is regulated by a several stress pathways acting in concert. In this study, we have identified a novel mechanism of regulation of a Rae1 family NKG2D ligand by proliferation stress. In proliferating B6 fibroblasts, Rae1e is induced at both the mRNA and protein levels, and in a manner that is not dependent on the DNA damage response or oxidative stress. Induction and maintenance of Rae1 expression is inhibited by growth factor starvation or any of numerous inhibitors of cell proliferation. Run-on transcription assays demonstrated that regulation is at the level of transcription. Ongoing studies suggest the role of specific cell cycle regulators as essential for Rae1 expression, and have probed their role in this process. This pathway implicates proliferation stress that occurs early in tumorigenesis and infections as a danger signal that induces the innate immune response.
A new subset of CD57+NKG2Chi NK cells is observed after HCMV infection infection (108.4)
Authors: Lopez-Verges Sandra , Milush Jeffrey , Schwartz Brian , Jarjoura Jessica , York Vanessa , Pandey Suchitra , Houchins J. , Miller Steve , Kang Sang-Mo , Norris Phillip , Nixon Douglas , Lanier Lewis 
Published: January 2023

Abstract
During human cytomegalovirus (HCMV) infection, there is a preferential expansion of Natural Killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of HCMV-infected cells. We recently showed that CD57+ NK cells within the CD56dimCD16+ NK cell compartment are highly mature. We hypothesized that human NK cells previously expanded in response to viruses or other pathogens will be marked by expression of CD57. Indeed, we observed in HCMV+ donors that NK cells expressing the activating NKG2C receptor are preferentially CD57+. These CD57+NKG2Chi NK cells have down-regulated the inhibitory NKG2A receptor and some inhibitory KIRs. These CD57+NKG2Chi NK cells respond better to activation through the NKG2C receptor. Furthermore, CD57+NKG2Chi NK cells expressed high amounts of LIR-1, another receptor that recognizes HCMV. Finally, in solid organ transplant recipients with symptomatic HCMV infection the percentage of CD57+NKG2Chi NK cells among the total NK cell population increased as the HCMV plasma viral load decreased. In these patients the NKG2C+ NK cells expanded and proliferated before becoming NKG2Chi and acquiring CD57 expression. Together, these results suggest that during HCMV infection, NKG2C+ NK cells expand to fight the infection, and after several divisions acquire CD57. In humans CD57 might provide a marker of "memory" or "terminally differentiated" NK cells that have been expanded in response to infection.
Role of the receptor-like protein tyrosine phosphatase CD148 in the T cell-independent antibody response (109.12)
Authors: Skrzypczynska Katarzyna , Zhu Jing , Weiss Arthur 
Published: January 2023

Abstract
Efficient elimination of a pathogen is dependent on both rapid and sustained antibody production by B cells. In contrast with conventional (B2) B cells, which produce antigen-specific antibody later in infection, B1 B cells generate natural antibodies and contribute to the T-cell independent (TI) antibody response. B cell activation and subsequent antibody secretion involve tyrosine phosphorylation, which is tightly regulated by protein tyrosine kinases (PTKs) and receptor-like protein tyrosine phosphatases (RPTPs). Previous studies from our lab have demonstrated that the RPTPs CD148 and CD45 have redundant positive regulatory roles in the development and antigen receptor signaling of B2 B cells by acting on on Src PTKs. However, the role of RPTPs in signal transduction in B1 B cells is not well understood. We have found that mice with a targeted deletion of the transmembrane domain of CD148 have an impaired IgM response when challenged with a TI antigen. This suggests that CD148 has a unique role in the TI response that cannot be compensated by CD45. Here, we use the mb1-cre transgenic mouse model as well as adoptive transfer experiments and in vitro analysis of B cell activation to characterize the function and specificity of CD148 in the B1 B cell response to TI antigen. These studies describe a previously unappreciated cell-autonomous role for CD148 in modulating signaling pathways that are important for the generation of TI antibody responses by B1 B cells.
Ghrelin stimulates cell proliferation in T cells (109.22)
Authors: Lee Junho 
Published: January 2023

Abstract
Ghrelin is a 28 amino acid acylated peptide, which is produced and secreted by X/A-like enteroendocrine cells of the stomach. We have recently demonstrated that ghrelin is expressed by various immune cells including T- and B-lymphocytes, monocytes and neutrophils. These immune cells have also been shown to express the ghrelin receptor, namely the growth hormone secretagogue receptor (GHS-R). In the present study, we have investigated the effects of ghrelin on T cell proliferation and its signaling through its cell surface receptor. We have found that ghrelin induces a modest increase in the proliferation of murine CD4+ T cells and T-cell lines. Western blot experiments have demonstrated that GHS-R ligation activates the external receptor activated kinases (ERK1/2) and Akt signaling pathways in a dose-dependent fashion. Moreover, we have also revealed the involvement of the PKC pathway in the phosphorylation of ERK1/2. The pro-proliferative effects of ghrelin through ERK1/2 appears to be mediated through the regulation of the expression of cell cycle proteins, cyclin D1, CDK4, cyclin E and CDK2 as well as Rb. Together, these data suggest that ghrelin promotes the cell proliferation of T cell via the activation of the PKC, PI-3-K, Akt and Erk1/2 signaling pathways and that this GHS-R signal appears to be essential but not sufficient for cell cycle progression.
SLP-2 deficiency in T cells is associated with decreased respiratory complex I levels and impaired TCR-dependent responses (109.27)
Authors: Christie Darah , Lian Dameng , Wang Hao , Hatch Grant , Madrenas Joaquín 
Published: January 2023

Abstract
We have previously reported that stomatin-like protein 2 (SLP-2) regulates human T cell activation through the antigen receptor. In human lymphoid tissues, SLP-2 is widely expressed in the thymus, lymph nodes and tonsils, and its expression is further up-regulated in response to lymphocyte activation. In T cells, SLP-2 is found in two pools: the most abundant is associated with mitochondria while a smaller pool is associated with the plasma membrane. To further investigate the role of SLP-2, we generated T cell-specific SLP-2 deficient mice. These mice had normal numbers of thymocytes and mature T cells. However, SLP-2 deficient T cells showed significantly less T cell activation in response to T cell stimulation in vivo and in vitro. Although SLP-2 deficient T cells did not show significant alterations in mitochondrial biogenesis, they had decreased levels of the NDUSF3, NDUFB8 and NDUFA9 subunits of complex I of the respiratory chain, suggesting a possible role for SLP-2 in regulating the stability of proteins involved in mitochondrial electron transport. SLP-2 deficient T cells also had less cardiolipin within detergent-insoluble microdomains, which may be required for proper respiratory chain assembly and function. Based on these results, we conclude that SLP-2 contributes to T cell activation, in part by regulating stability of complex I of the respiratory chain and sustaining the metabolic requirements for T cell activation.
Role of TRAF3 in TCR signaling (109.30)
Authors: Yi Zuoan , Stunz Laura , Bishop Gail 
Published: January 2023

Abstract
Adaptor molecules play critical roles during signal transduction. TNF receptor associated factor 3 (TRAF3) is involved in a variety of signaling pathways in both innate and adaptive immunity. Recently, we demonstrated that TRAF3-deficient T cells exhibit severely impaired function, that TRAF3 associates with the TCR complex, and TRAF3 plays essential roles in TCR signaling pathways. Here, we find that TRAF3 affects diverse signaling events downstream of the TCR. Upregulation of activation markers in TRAF3-deficient T cells is slower than in Wt T cells, but TCR internalization is not affected. Furthermore, the deficiency of TRAF3 does not affect the recruitment of ZAP70 and Lck after TCR stimulation, but phosphorylation of ZAP70 is decreased. This result suggests that TRAF3 facilitates the interaction between Lck and ZAP70, and without TRAF3, Lck does not phosphorylate ZAP70 efficiently. Additional studies on how TRAF3 interacts with the TCR complex are ongoing.
The ERM family protein Ezrin associates with the JNK signaling complex to regulate its activation and antigen-dependent B cell survival. (109.7)
Authors: Parameswaran Neetha , Liggett Luther , Bagheri Nayer , Gupta Neetu 
Published: January 2023

Abstract
Antigen binding to the B cell antigen receptor (BCR) results in initiation of a highly orchestrated series of enzymatic reactions and protein-protein interactions that transmit the signals for B cell survival and proliferation. The highly conserved Ezrin-Radixin-Moesin (ERM) family members are thought to regulate lymphocyte activation via their membrane-actin crosslinking property, which is in turn regulated by phosphorylation of a conserved threonine residue at their C-terminus. Here, we report a novel signal transduction axis that links antigen-dependent tyrosine phosphorylation of ezrin with activation of the c-Jun N-terminal kinase (JNK). BCR ligation induces phosphorylation of Y353 in ezrin, a residue that is not conserved in other ERM proteins. Phosphorylation of Y353 is dependent on Src and Syk family kinase activity, occurs preferentially on the open conformer of ezrin, and correlates with the strength of BCR signaling in mature B cell subsets. Tyrosine phosphorylated ezrin associates with components of the JNK signaling complex in response to BCR stimulation. A non-phosphorylatable (Y353F) mutant of ezrin acts in a dominant negative manner to specifically impair antigen-induced JNK activation, and reduces B cell survival. Our results demonstrate a unique and novel signaling role for ezrin in regulating antigen-dependent JNK activation and B cell survival.
Discovery and characterization of novel distal regulatory elements involved in the regulation of CIITA promoter three. (109.9)
Authors: Lohsen Sarah , Boss Jeremy 
Published: January 2023

Abstract
Major histocompatibility complex class II (MHCII) molecules on B cells display antigenic peptides that trigger CD4 T cells specific for the same antigen to activate naïve B cells to differentiate into plasma cells. The MHCII transactivator, CIITA, is highly expressed in B cells (corresponding to MHCII expression), but silenced in transition to mature plasma cell. Understanding CIITA regulation can elucidate details of the generation of humoral immunity. Work has been done describing the role of proximal elements in the CIITA locus and their contribution to the regulation of CIITA. Recent experiments have shown that there are elements involved in CIITA regulation in non-immune cells that are much more distal to the promoter than previously thought, up to 50kb from the active promoter. However, no data on these or other elements in B cells and plasma cells were described. Using a medium throughput PCR-based DNaseI hypersensitivity assay to screen across the CIITA locus, regions of accessible chromatin were characterized that distinguish between the active and silenced state of CIITA expression. Computational methods reveal key regions of cross-species homology and transcription factor binding. These methods together identify novel distal regulatory elements that will be confirmed using a Bacterial Artificial Chromosome (BAC) system.
Macrophages differentiation confers resistance to HIV-Vpr induced apoptosis (110.10)
Authors: Busca Aurelia , Kumar Ashok 
Published: January 2023

Abstract
Macrophages represent major viral reservoirs during HIV infection, because they are long lived and resistant to HIV cytopathic effects. We have evaluated the role of Bcl2 and IAPs (inhibitors of apoptosis), the main families of antiapoptotic proteins, in macrophage resistance during HIV infection by using the HIV accessory protein Vpr as a study model for apoptosis. Our results show that human monocytes are sensitive to Vpr but develop resistance following differentiation into macrophages. Vpr efficiently down-regulated cIAP1 and Bcl2 in sensitive monocytes but not in macrophages, suggesting that these molecules could be implicated in the enhanced resistance of macrophages to HIV-Vpr apoptosis. However, Bcl2 inactivation with the HA14-1 inhibitor was able to induce cell death on its own, with no impact on susceptibility to Vpr apoptosis. By using siRNA to knock down the expression of IAP1 and IAP2 proteins and SMAC mimetic to induce their degradation, macrophages could be sensitized to Vpr-induced cell death. Our results suggest that IAPs and not Bcl2 family confer a resistant phenotype that is relevant for macrophage survival in the context of HIV infection. Modulation of the apoptotic pathway during monocyte differentiation provides insight into the possible mechanisms for viral reservoirs persistence in macrophages and into potential therapeutic approaches to target antiapoptotic genes.