bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAG-1 (Recombination Activating Gene-1) protein is closely related to herpes virus recombinases: Implications for the origins of the acquired immune system. (105.20)
Authors: Dreyfus David 
Published: January 2023

Abstract
The acquired immune system results from recombination of germ-line DNA V(D)J signal sequences by the RAG-1 recombinase. RAG-1 is a dde magnesium binding recombinase related to both retroviral integrases and transposases. However the closest phylogenetic relative to RAG-1 appears to be a family of recombinases encoded by the herpesviridae termed the DBP (DNA binding proteins) that catalyze strand exchange and possibly other recombination events during herpes virus replication. Both the dde magnesium binding triad and the nonamer binding regions of RAG-1 are present and conserved in the DBP. These observations suggest that initially RAG-1 arose from an ancient insertion of a herpes-like infectious agent into a deuterostome genome prior to the origins of the acquired immune system. The author proposes a model in which the primordial RAG-1 recombinase was selected through its ability to promote viral immune responses through innate immune receptors in ancient deuterostomes prior to the origins of V(D)J recombination.
Bolstering the TG-resident HSV-1-specific CD8+ T cell response via IL-10R blockade (105.26)
Authors: St. Leger Anthony , Hendricks Robert 
Published: January 2023

Abstract
Herpes simplex virus type 1 (HSV-1) infection of mouse corneas leads to establishment of a latent viral infection in sensory neurons of the trigeminal ganglion (TG). Activated CD8+ T cells enter the TG during acute infection and are retained in close apposition to neurons during latency. Fifty percent of the CD8+ T cells in the infected TG of C57BL/6 mice recognize an immunodominant epitope on HSV-1 glycoprotein B (gB498-505), while the remaining CD8+ T cells target subdominant epitopes on 11 other viral proteins. Although both populations appear to be stimulated throughout latency, gB498-505-CD8s show increasing functionality (lytic granule release and IFN-γ and TNF-α production) during latency and appear to have a primary role in blocking HSV-1 reactivation from latency. In contrast, TG CD8+ T cells reactive to subdominant epitopes lose functionality during latency. Three weeks of in vivo anti-IL-10R mAb treatment minimally affected the gB498-505-specific TG resident CD8+ T cells, but did dramatically increase in the number of functional CD8+ T cells specific for subdominant epitopes, and improved control of HSV-1 latency in ex vivo TG cultures. We conclude that CD8+ T cells specific for subdominant epitopes are suppressed in the TG by host secretion of IL-10. Our findings suggest the exciting possibility that rescue from IL-10 suppression will expand the functional repertoire of HSV-specific CD8+ T cells and reduce the likelihood of viral reactivation from latency.
HLA targeting efficiency correlates with human T-cell responses magnitude and with mortality from Influenza-A infection (105.30)
Authors: Hertz Tomer , Oshansky Christine , Roddam Philippa , DeVincenzo John , Caniza Miguela , Jojic Nebojsa , Mallal Simon , Phillips Elizabeth , James Ian , Halloran M. , Thomas Paul , Corey Lawrence 
Published: January 2023

Abstract
Experimental and computational evidence suggests that human leukocyte antigens (HLAs) preferentially bind conserved regions of viral proteins, a concept we term “targeting efficiency,” and that this preference can provide improved clearance of infection in several viral systems. One potential advantage of targeting conserved regions of a virus is the higher likelihood of cross-reactive protection from other viral strains, including those newly introduced, such as pH1N1. We hypothesized that individuals that targeted less conserved regions of influenza- A viruses would have weaker T-cell responses following infection with pH1N1. To test this hypothesis, T cell responses to A/H1N1 (2009) were measured from PBMCs obtained from a household cohort study performed during the 2009-2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFNγ ELISpot responses (p=0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r=0.37, p=0.031). Interestingly, these are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. The computational tools utilized in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons.
Modulation of Anti-Viral and Anti-Bacterial B Cell Responses in Super-infections (105.36)
Authors: Wolf Amaya , Strauman Maura , Mozdzanowska Krystyna , Williams Katie , Shen Hao , Weiser Jeffrey , Erikson Jan 
Published: January 2023

Abstract
Respiratory tract infections (RTIs) with influenza virus are a major global health concern, and together with secondary bacterial infections can cause fatal pneumonia. As B cells contribute to protection through the production of antibodies (Abs), we investigated how concomitant viral-bacterial super-infections alter the generation and maintenance of protective B cell responses in RTIs. We established two models of co-infections with influenza A virus (IAV) and Streptococcus pneumoniae (Sp). The first reflects individuals with a viral RTI that go on to contract a subsequent bacterial infection; the second considers individuals that are asymptomatic carriers of bacteria prior to contracting a viral RTI. Mice infected with Sp following IAV exhibit increased signs of morbidity, whereas mice carrying Sp prior to IAV exhibit less morbidity. Super-infection with Sp following -but not prior to- IAV significantly increases anti-viral serum Abs. Furthermore, the kinetics of the germinal center response and the ASC response in the lung-draining mediastinal lymph node and in the lungs are altered. We demonstrate that anti-viral Ab-specificities and -isotypes are differentially affected. Interestingly, the Ab response to Sp is not impacted in either scenario, suggesting distinct regulatory mechanisms for anti-viral and -bacterial B cell responses in these co-infection models.
Programmed Death-Ligand 1 (PD-L1) expressed on Herpes Simplex Virus Type 1 (HSV-1) infected neurons limits survival of CD8 T cells specific for subdominant epitopes. (105.45)
Authors: Jeon Sohyun , St. Leger Anthony , Cherpes Thomas , Sheridan Brian , Hendricks Robert 
Published: January 2023

Abstract
CD8 T cells that reside in the trigeminal ganglia (TG) of HSV-1 latently infected mice maintain viral latency through persistent interaction with infected neurons. Interestingly, CD8 T cells in TG of C57BL/6 mice exhibit a 1:1 ratio of cells recognizing subdominant versus an immunodominant (gB498-505) HSV-1 epitope. We investigated the role of Programmed Death-1 (PD-1) and its ligand, PD-L1 (B7-H1) in determining this ratio. We found that subdominant CD8 T cells in the TG 1) preferentially express PD-1, 2) are functionally compromised, and 3) proliferate and undergo apoptosis at a higher rate than gB498-505-specific CD8 T cells. Moreover, PD-L1 is preferentially expressed on neurons with a high latent viral load, and its expression is regulated by interferon-γ. In B7-H1-/- mice and bone marrow chimeras lacking PD-L1 only on parenchymal cells, the ratio of subdominant cells to gB498-505-specific cells was dramatically increased (4:1). This was due to increased survival of PD-1+ subdominant CD8 T cells that remained non-functional, and did not augment CD8 T cell protection from HSV-1 reactivation in ex vivo TG cultures. We conclude that PD-1/PD-L1 interaction regulates the survival, but not the function of CD8 T cells specific for subdominant HSV-1 epitopes in latently infected TG. Blocking this interaction alone is not sufficient to reduce HSV-1 reactivation from latency, but might be effective if combined with blockade of other suppressor molecules.
High frequency of lytic EBV-IAV cross-reactive CD8 T cells in EBV sero-negative adults (105.47)
Authors: Watkin Levi , Aslan Nuray , Gil Anna , Luzuriaga Katherine , Selin Liisa 
Published: January 2023

Abstract
The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a life-long infection. The clinical presentation of EBV infection can range from asymptomatic to severe, occasionally fatal, acute infectious mononucleosis (IM). There is also a strong causal relationship between EBV infection and common malignancies, including carcinoma’s, and Burkitt’s lymphoma. However it is unknown why 5-10% of adults remain EBV-sero-negative (EBV-SN), despite the fact the virus infects the vast majority of the population and is actively shed at high titers even during chronic infection. Here, we show that EBV-SN HLA-A2+ adults possess cross-reactive IAV-GIL/EBV-GLC memory CD8 T-cells that show highly unique properties. These IAV-GIL crossreactive cells preferentially expand, and produce cytokines to, EBV antigens with high avidity. Additionally they are capable of lysing EBV-infected targets and show the potential to enter the mucosal epithelial tissue where infection is thought to initiate. They also possess a T-cell receptor (TCR) repertoire that differs by both organization and CDR3 usage from that in EBV-seropositive (EBV-SP) donors. Our results imply that heterologous immunity may protect EBV-SN adults against the establishment of productive EBV infection, and thus be the first demonstration of heterologous immunity between unrelated pathogens in sero-negative human subjects.
Severity of Epstein-Barr Virus (EBV)-induced infectious mononucleosis (IM) correlates with the frequency of crossreactive influenza A virus-M1 and EBV-BMLF-1-specific CD8 T cells (105.48)
Authors: Selin Liisa , Watkin Levi , Luzuriaga Katherine , Aslan Nuray 
Published: January 2023

Abstract
During EBV-associated IM influenza A-specific crossreactive memory T cells are 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, BMLF-1280 (17/29) and BRLF-1190 (19/20). Furthermore, 11/22 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF1 and -BMLF1 responses. Disease severity of IM did not correlate with viral load, but instead directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF-1-specific CD8 cells, as well as IAV-M1, EBV-BMLF-1 specific CD8 cells, but not BRLF1 responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in all three tetramer-positive populations suggesting that TcR selection is driving disease outcome. Consistent with IAV-M1 and EBV-BMLF1 responses driving increased immunopathology was the observation that patients with severe disease had significantly more IAV-M1 and EBV-BMLF1 cells producing IFNg/MIP1-b in response to antigen as compared to patients with mild disease. These results suggest that T cell crossreactivity can impact T cell selection and function and ultimately disease outcome. Insights on these issues are important for the intelligent design of vaccines and to develop effect therapeutic interventions for virally induced disease.
The frequency of circulating HSV-2 antigen-specific T cells and antibodies is stable and remains unchanged by HSV-2 reactivation in infected individuals (105.54)
Authors: Skoberne Mojca , Larson Shane , Zielinski Veronica , Long Deborah , Warren Terri , Lundberg Amy , Hetherington Seth , Flechtner Jessica 
Published: January 2023

Abstract
HSV-2 infection is characterized by chronic intermittent shedding of virus and episodic clinical outbreaks. T cells and antibodies play a critical role in controlling the infection. While patients possess T cell reactivity to multiple HSV-2 antigens, reactivity to specific antigens may be associated with control of clinical disease. Recurrence of clinical disease is episodic, but little is known about the temporal variation in peripheral T cell responses to HSV-2. T cell and antibody responses to two antigens previously associated with asymptomatic infection were studied among 27 HSV-2 seropositive individuals with a history of HSV outbreaks by IFN-γ ELISPOT and endpoint titer antibody ELISA, respectively. Peripheral blood was collected 4 times, 3 weeks apart and within 48 hours of any genital lesion outbreak. Patients were categorized as high or low responders. None of high and 9 of 23 low T cell responders experienced clinical outbreaks. Immune responses did not vary significantly during the study period or during clinical outbreaks. The correlation of immune response and subclinical disease is currently under evaluation. These results indicate that in chronic HSV-2 infection, levels of peripheral T cells and antibodies remain consistent over time and are not boosted during viral outbreaks. This supports the hypothesis that a vaccination strategy to increase T cell responses to select HSV-2 antigens may provide a therapeutic benefit to the patients.
Immunization with MOG fused to a novel single chain fragment variable (scFv) for murine DEC-205 suppresses allergic experimental encephalomyelitis (EAE) in mice. (106.12)
Authors: Ring Sabine , Enk Alexander , Mahnke Karsten 
Published: January 2023

Abstract
The antigenreceptor DEC-205 is expressed by Dendritic cells (DC) and greatly increases antigen presentation. We have shown that in vivo loading of DC with antigen via anti-DEC-205:antigen conjugates induces immunosuppressive regulatory T-cells (Treg). Therefore we set out to create single chain fragment variables (scFv) specific for DEC-205 fused with the EAE antigen MOG, to target non-activated DC for induction of tolerance to EAE in vivo. A non-binding anti-b-gal scFv:MOG was created as control. ScFv:MOG fusions proteins were expressed and purified, and immunohistochemical staining of cytospins from isolated CD11c+ cells displayed a positive staining for DEC-scFv, colocalizing with MHC class II. For functional testing DEC-scFv:MOG was injected into mice. Lymph node DC were isolated thereafter and cocultivated with MOG-specific (2D2) T-cells. Strong T-cell proliferation was induced by DC from mice injected with DEC-scFv:MOG in contrast to controls. When analyzing the T-cell populations in DEC-scFv:MOG injected mice, we found enhanced numbers of CD4+CD25+FoxP3+ Treg (16% of CD4) as compared to control animals (10% of CD4). Most importantly, when EAE was induced in either DEC-scFv-MOG-injected or in control mice, none of the DEC-scFv:MOG injected mice developed EAE symptoms. In contrast, all animals in the control group developed a severe EAE. Thus, these data indicate that targeting of MOG to steady state DC in vivo prevents EAE by a Treg-driven mechanism.
Internalization of Poly(dG)-antigens by dendritic cells (106.14)
Authors: Narciso Jo Erika , Toussaint Hélène , Erdos Geza , Donahue Cara , Falo Louis 
Published: January 2023

Abstract
Effective vaccine design depends in part on the ability to target specific antigens (Ag) to Ag presenting cells (APCs), including dendritic cells (DCs). Further, to generate effective antitumor and antiviral immunity, vaccine platforms should enable efficient MHC class I and class II restricted antigen processing leading to synergistic CD4 and CD8 T-cell responses. To facilitate targeted vaccine delivery, we have developed Poly(dG)-protein Ags. These Ag conjugates have the potential to greatly increase vaccine efficiency by inducing spontaneous aggregation of Ag into particulate complexes with intrinsic adjuvant function. The resulting particulate structure includes exposed phosphate groups with affinity for scavenger receptors expressed by APCs. We have successfully conjugated Poly(dG) residues to the model Ag ovalbumin (OVA) and found that Poly(dG)-OVA can be rapidly endocytosed, and efficiently presented to class II-restricted T cells, and cross-presented to class I-restricted T cells in vitro and in vivo. We compared DCs internalization of Poly(dG) conjugated and unconjugated Ag using confocal microscopy and found that Poly(dG)-OVA bound to the cell surface of DCs with higher affinity and was internalized several times more efficiently than Ag alone. These results suggest that coupling Poly(dG) to Ags enables efficient APCs targeting. Understanding the mechanisms of internalization, processing, and presentation of Poly(dG)-Ags will contribute to future vaccine design.
Biodegradable polymer, PLGA, is an efficient vehicle for class II MHC-restricted antigen presentation and the induction of DC maturation (106.15)
Authors: Lee Chong-Kil , Park Dong-Eun , Kim Uji , Park Chan-Su , Kim Ki-Hyang , Im Sun-A 
Published: January 2023

Abstract
The antigen presentation and maturation activities of antigen-encapsulated biodegradable nanoparticles were compared with that of antigen-antibody immune complexes. Dendritic cells (DCs) were allowed to uptake ovalbumin (OVA) via pinocytosis, phagocytosis or endocytosis, and then the levels of MHC-restricted OVA peptide presentation were measured using OVA specific CD4 and CD8 T cells. Poly(D,L-lactic acid-co-glycolic acid, PLGA)-encapsulated OVA (pOVA) and OVA-IgG complexes (OVA-IC) were equally efficient in inducing MHC class I and II-restricted OVA peptide presentation. Comparison of the amount of OVA peptide presentation showed that class II-restricted presentation pathways were robust process compared to class I-restricted presentation pathways. Maturation inducing activities of pOVA and OVA-IC were also examined. pOVA was as efficient as or better compared to OVA-IC in inducing the expression of cell surface molecules such as class II, CD80, CD86, and the secretion of cytokines IL-6, IL-1β and TNF-α. These results show that the biodegradable polymer, PLGA, is an efficient vehicle not only for class II-restricted antigen presentation but also for induction of DC maturation. The present study also shows that in exogenous antigen presentation by DCs, cross presentation is a much weaker phenomenon compared to MHC class II-restricted presentation.
Intestinal dendritic cells survey circulatory antigens prior to induction of regulatory CD8α/β T cells (106.2)
Authors: Song Joo Hye , Change Sun Young , Guleng Bayasi , Cotoner Carmen , Arihiro Seiji , Karp Christopher , Kweon Mi-Na , Sharpe Arlene , Bhan Atul , Terhors Cox , Reinecker Hans-Christian 
Published: January 2023

Abstract
Background: Antigens in the intestine transition from fenestrated capillaries through the lamina propria into the draining lymphatics, but whether or how this process controls mucosal immune responses is unclear. CX3CR1+ DCs are uniquely positioned for the recognition of environmental and circulatory antigens in the lamina propria as they interact with both the epithelium and with the capillary vessel system in the lamina propria. Results: We demonstrate that small intestinal CX3CR1+ dendritic cells (DCs) acquire and process both circulatory and luminal antigens in the lamina propria. Through cross-presentation of antigen, CX3CR1+ DCs induce differentiation of IL-10 secreting CD8α/β T regulatory cells, that is dependent upon Programmed Death ligand 1/2 and its counter-structure PD1 of CD8 T cells. Differentiated CD8+ T regulatory cells represent a subset of intraepithelial lymphocytes (IELs) which express the specific adhesion molecule CD103. The CD8+ Tregs inhibit antigen specific CD4+ T cell activation through IL-10 secretion and prevent CD45RBhigh CD4 T cell-mediated small intestinal inflammation. Conclusion: Our finding shows that the lamina propria CX3CR1+ DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally- absorbed antigens leading to the induction of CD8+T regulatory cells, which govern tolerance in the mucosal immune system.
Central and overlapping role of cathepsin B and Inflammasome Adaptor ASC In antigen presenting function of human dendritic cells (106.22)
Authors: Dhodapkar Kavita , Guo Xiuyang 
Published: January 2023

Abstract
Inflammasomes are molecular platforms that trigger processing of proinflammatory cytokines. Inflammasomes have also been implicated in regulating adaptive immunity. How inflammasome activation relates to the maturation and antigen presentation in human dendritic cells (DCs) is unknown. Here we show that DC maturation stimuli lead to rapid but transient activation of caspase-1 in human monocyte-derived DCs. RNAi mediated inhibition of the inflammasome component ASC leads to marked inhibition of the capacity of lipopolysachharide (LPS)-matured DCs to stimulate antigen-specific T cells. RNAi mediated inhibition of Cathepsin B (CatB) also similarly inhibits the capacity of human DCs to stimulate immunity. The defective ability of ASC or CatB deficient DCs to stimulate T cells is independent of inflammasome-mediated processing of inflammatory cytokines such as IL1 and includes DCs loaded with preprocessed peptide. Gene expression profiles of ASC or CatB deficient human DCs show marked overlap with down-regulation of several genes implicated in DC function, but differ from those recently shown to be altered in ASC deficient murine DCs. These data demonstrate an important role for ASC and CatB in regulating function of human DCs. In addition to their well-studied roles in the cytosol (such as inflammasome and lysosome function), surprisingly overlapping effects of these proteins on gene expression may also contribute to their roles in the immune system.
The MHC class I antigen processing components TAP and ERAAP sculpt the MHC class II-restricted self peptidome and modulate the CD4+ T cell receptor repertoire impacting T helper responses to microbial pathogens. (106.24)
Authors: Spencer Charles , Dragovic Srdjan , Niu Xinnan , Sette Alessandro , Link Andrew , Joyce Sebastian 
Published: January 2023

Abstract
Humans deficient in TAP or ERAAP function present with recurrent infections despite elevated CD4+ T cell numbers. As CD4+ T cells regualte multiple immune response, their actions are critical to anti-microbial responses. Recently, studies have identified a role for TAP and ERAAP in generating influenza, Listeria and minor histocompatibility antigen peptides recognized by CD4+ T cells. Though the MHC class I-restricted self peptidome is known to be regulated by TAP and ERAAP, the affect on MHC class II-restricted self peptidome is unknown. Here we show that the MHC class II-restricted self peptidome is dramatically altered by the activities of TAP and ERAAP. The CD4+ T cell repertoire correspondingly had profound alterations in the diversity of the TCR CDR3 region that defines antigen specificity. This altered CD4+ T cell repertoire led to altered class II-restricted peptide recognition pattern in TAP-deficient mice. Though some peptides were recognized at an enhanced magnitude, the recognition of others was either lost or newly acquired. Taken together these data suggest that TAP and ERAAP sculpt class II-restricted peptidomes and thereby affect the CD4+ T cell repertoire. The recognition of a new, yet overlapping, immunome by TAP deficient CD4+ T cells demands further investigation to understand the extent of interaction between the MHC class I and class II antigen processing pathways and their effects on anti-microbial responses particularly in TAP deficient individuals.