bluuebunny/crossref_metadata_2025_split huggingface dataset:
Graft plasmacytoid dendritic cells improve thymic function in allogeneic hematopoietic cell transplantation
Authors: Zhu Jingru , Wang Yitong , Antonova Alina Ulezko , Li Yiwen , Giver Cynthia R , Hassan Mojibade , Waller Edmund K 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is a well established cure for a variety of hematologic diseases. However, graft-versus-host disease(GVHD) remain the primary obstacles to successful transplant. GVHD results from donor T-cell recognition of a genetically disparate recipient. Thymus has been recognized as a recipient tissue that can be severely damaged by GVHD. Plasmacytoid dendritic cells(pDCs) is a distinct subset of DC, which have both immunogenic and tolerogenic effect in allo-HSCT, licensed by the microenvironment to respond to the milieu in which they migrate. Impaired thymic DC has been the major causation of dysfunctional thymic negative selection, thus generating allo-reactive T cells and GVHD. To further demonstrate pDCs from the graft are migrating to thymus to protecting host from GVHD. We transplanted B10.BR mouse with pDCs from MHC mismatched GFP-labeled C57/B6 mouse, along with hematopoietic stem cells and T-cells from normal C57/B6 mouse. The results from the confocal imaging suggest that pDCs are migrating to thymus 14 days after allo-HSCT. CCR9 expression is important for pDCs migrating to thymus. We transplated mice with either wild type pDCs or CCR9 knock out pDCs. Survival rate is significantly lower in group transplanted with CCR9-knockout pDCs suggesting thymus is a critical place for pDCs to induce tolerogenic response. We also tranplanted wild tipe pDCs with thymectomized host and normal host. Thymectomy group have better survival rate compared to non-thymectomized group, further confirming the association between pDCs and thymus. Improved thymic function post transplant with pDCs from the graft may have a potential to decrease GVHD.
Carbomer-based adjuvant potentiates CTL immunity by enhancing cross-presentation of antigens by NOX2 and TAP-dependent mechanisms
Authors: Lee Woojong , Bakke Brock , Sonsalla Shelly , Sanchez Darren , Reyes Leticia , Iyer Gopal , Suresh M. 
Published: January 2023

Abstract
We have previously showed that a carbomer-based adjuvant (CBA), Adjuplex® (ADJ) enhanced systemic and mucosal CD8 T cell responses to non-replicating antigens. Here, we investigated the molecular mechanism(s) of how the CBA enhance cross-presentation of antigens by dendritic cells (DCs). We found that ADJ enhanced cross-presentation of antigens in DCs by several mechanisms, including augmenting antigen degradation, reducing endosomal acidity, promoting antigen localization to early endosomes and increasing ROS production leading to escape of antigen from endosomes to the cytosol. Additionally, we find that ADJ-induced cross-presentation of antigens by DCs required NOX2 and TAP1. Taken together, we propose that ADJ enhances cross-presentation of antigens by promoting NOX2-dependent ROS production leading to endosomal antigen leakage, proteolysis of antigen by proteasomes and TAP-dependent peptide transport into MHC-containing cellular compartment. Thus, our studies have revealed a novel mechanism for ADJ-induced cross-presentation of antigen, highlighting the significance of incorporating CBA as a vaccine adjuvant to elicit strong cytotoxic T cell responses.
Determinants of TCRα-β chain pairing in generating TCR diversity
Authors: Tanno Hidetaka , Gould Timothy M , Durrett Russell E , McDaniel Jonathan R , Cao Wenqiang , Gollihar Jimmy , Steven Cate , Tanno Yuri , Ellington Andrew D , Ippolito Gregory C , Hildebrand William , Georgiou George , Goronzy Jorg J 
Published: January 2023

Abstract
Advances in next-generation sequencing have allowed insights into the enormous diversity of the human T cell receptor (TCR). Earlier studies have suggested that ~108 unique TRB genes exist at the periphery. In contrast, the factors that determine the pairing of TCRα and TCRβ chains have remained elusive due to the lack of high-throughput single-cell sequencing technology. We have developed a high-throughput single-cell sequencing technology that enables identification of &gt;3×104 paired TRA:TRB sequences per sample and have conducted sequencing of naïve and memory CD4+ and of total T cells from 15 healthy individuals, including six pairs of monozygotic twins. We found that the frequencies of TRAV:TRBV pairing are essentially determined by the frequencies of the individual gene segments, suggesting the absence of structural constraints in the pairing of the α and β chains. Twins are more similar in the frequencies of TRAV and TRBV combinations than are unrelated individuals, but this difference was explained by a genetic influence on AV and BV gene segment frequencies. Twins and unrelated individuals were compared for the sharing of identical TCR sequences. TRA sequence sharing among twins was comparable to that among unrelated individuals, but TRB sharing was significantly higher in twins. Sharing of the entire TCR was regularly found in twins but not detected for naïve CD4+ T cells from unrelated individuals. Results were similar for naïve and memory T cells, with the genetic influence more prominent in memory T cells, suggesting the additional influence of peripheral selection. In support of this interpretation, the sharing of identical TCR sequences in unrelated individuals correlated with the number of shared MHC class II alleles.
HIV-1-specific B cell immune responses in Rhesus Macaques induced by early region deleted-Ad5 vectors
Authors: sangare Kotou , Hogge Christopher , Hait Sabrina Helmold , Hoang Tanya , Robert-Guroff Marjorie , Thomas Michael A 
Published: January 2023

Abstract
As a vaccine delivery vector, Adenovirus (Ad) is recognized for its ability to prime immune responses against HIV and other infectious agents. We reported that early region 1B55k (E1B55k) deleted vector induced cellular immunity, transgene-specific antibodies and innate immune signals including chemokines, cytokines and NKG2D ligands MIC A/B in immunized mice. However, the immune priming ability of E3-E1B55k-E4orf1 and E3-E1B55k- E4orf1-4deleted Ad vectors is unknown. Here we compared HIV-specific immune responses generated by E3deleted, E3-E1B55k, E3-E1B55k-E4orf1and E3-E1B55k-E4orf1-4deleted Ad5 vectors encoding full-length single-chain HIVBalgp120 linked to the D1 and D2 domains of rhesus macaque (RM) CD4 (rhFLSC). RMs were immunized twice mucosally with each vector. Blood and rectal tissue were collected at pre and 2-week post-immunization time points. The frequency of plasmablasts (PB)/plasma cells (PC), memory B cells, and antibody secreting cells and antibody titers were assessed by flow cytometry, ELISpot and ELISA, respectively. All vectors induced increased frequencies of rectal PB, PC and rhFLSC specific memory B cells. rhFLSC specific IgA and IgG secreting cells were detected in all immunized macaques; the IgA secreting cells were significantly increased compared to pre values. This was accompanied by elevated levels of IgG, IgG1 and IgA serum antibodies. In summary all four vectors induced B cells responses while retaining replicability. Moreover, the largest deletion, E3-E1B55k-E4orf1-4, improved the transgene carrying capacity of the Ad vector while maintaining the ability to induce B cell immunity important for protective efficacy.
Rainbow trout as a model for the study of neuroimmune interactions in the nasal mucosa
Authors: Salinas Irene , Sepahi Ali , Kraus Aurora , Das Pankoj 
Published: January 2023

Abstract
Many pathogens exploit the olfactory route to infect the lower respiratory tract or the central nervous system. Understanding the mechanisms by which the nasal mucosa halts pathogen progression is vital for the control of many human diseases. We have recently developed a model for the study of neuroimmune interactions in the olfactory organ of rainbow trout based on our initial discovery of a nasopharynx-associated lymphoid tissue in bony fish. Our studies indicate that viruses activate neurons in the olfactory epithelium and olfactory bulb of rainbow trout and that neuronal-viral interactions are required for the onset of ultra-rapid innate immune responses. These responses, that occur within minutes, have been overlooked thus far, and are characterized by the influx of non-conventional CD8 T cells that express TCRa/b. Further studies indicate that these response occur in response to a wide-range of microbial stimuli, albeit at lesser magnitude than in the case of live viruses. Current research efforts in our laboratory involve the validation of this model using human-relevant pathogens and vaccines such as the Flu vaccine. These results underscore the importance of understanding neuronal immune responses to pathogens and vaccines in order to develop better immunotherapies that exploit the nasal route.
Segregation of chicken MHC-Y haplotypes in high and low antibody selected lines provides evidence that MHC-Y contributes to the genetics of immune responses
Authors: Zhang Jibin , Goto Ronald M , Honaker Christa F , Siegel Paul B , Miller Marcia M 
Published: January 2023

Abstract
MHC-Y is a second genomic region in chickens containing genes encoding highly polymorphic MHC class I molecules. MHC-Y class I molecules have a distinctive surface distribution of polymorphic residues. The function of MHC-Y class I molecules is unknown. To begin to determine whether genetic differences at MHC-Y influence immune responses, we have defined the MHC-Y haplotypes segregating in the Virginia Tech high antibody (HAS) and low antibody (LAS) lines. HAS and LAS have been selected for 45 generations for high and low antibody responses to sheep red blood cells, respectively. The HAS and LAS lines are known from previous studies to differ at a number of loci that influence immune responses, including the classical MHC-B region. We MHC-Y typed the HAS and LAS lines at the 44th and 45th generation using a microsatellite sequence found immediately upstream of the MHC-Y class I gene start sites. Typing revealed the presence of five MHC-Y haplotypes overall. Two haplotypes were found only in the HAS line. The frequency of one haplotype was 60%. In LAS, three other haplotypes were common. The separation of different MHC-Y haplotypes in the HAS and LAS lines suggests that MHC-Y locus is another polymorphic genomic region changing in response to selection for high and low antibody phenotypes. This finding is among the first linking MHC-Y genetics to immune responses in chickens.
Supported in part by USDA NIFA Grant 2016-10247.
Sex-specific DLA Class II haplotypes are associated with primary hypoadrenocorticism in Standard Poodle dogs
Authors: Treeful Amy , Rendahl Aaron , Friedenberg Steven 
Published: January 2023

Abstract
Autoimmune Addison’s Disease (AAD) is a life-threatening endocrine disorder that occurs spontaneously in humans and dogs and whose clinical features are highly similar between the species. Associations between MHC class II genes and AAD have been shown in several human studies. Our goal was to identify MHC class II associations with AAD in a large population of Standard Poodles, a breed highly predisposed to AAD. We sequenced exon 2 of the class II genes DRB1, DQA1, and DQB1 in 110 affected and 101 unaffected Standard Poodles and tested for association with AAD. Two haplotypes were found to confer risk of developing AAD in a gender-specific manner: 015:01-006:01-023:01 in males (□2 p = 0.03, OR 2.1) and 009:01-001:01-008:011 in females (□2 p = 0.02, OR 8.43). Sex-specific associations have been previously described in human populations, but this is the first report of this kind in dogs. Consistent with findings in other studies, we also found the DQA1*006:01 allele (□2 p = 0.04) to be associated with AAD in males independent of haplotype. In females, the haplotype 009:01-001:01-008:011 appears to confer a very high risk for developing AAD, though its frequency was rare (9 of 124 females) in our study population. Further studies are warranted to assess the usefulness of this haplotype as a genetic risk marker for AAD in female Standard Poodles. Our findings highlight the importance of evaluating MHC class II-disease associations in large populations, and accounting for both gender and population structure in order to uncover clinically relevant associations.
Autoreactive potential of universal influenza vaccines
Authors: McGargill Maureen Ann , Pillai Meenu R , Chang Ti-Cheng , Crawford Jeremy , Keating Rachael , Labombarde Jocelyn , Lewis Carlessia , Guthmiller Jenna , Li Quan_Zhen , Wilson Patrick C , Thomas Paul 
Published: January 2023

Abstract
A universal influenza vaccine could save millions of lives in the event of a deadly pandemic. It is not clear why antibodies specific for conserved regions of influenza viruses are so rare. One possibility is that these antibodies have a higher potential to cross-react to self-proteins, and therefore B cells that generate these antibodies are deleted through tolerance mechanisms. Therefore, we examined whether cross-reactive influenza antibodies had a higher potential to be autoreactive than antibodies specific for one subtype of influenza. We previously demonstrated that H3N2-vaccinated mice treated with a low dose of rapamycin had more cross-reactive influenza antibodies and were better protected against subsequent lethal infections of multiple subtypes. Thus, we utilized rapamycin to increase the frequency of influenza cross-reactive antibodies, and tested whether these antibodies were more reactive to self-proteins than strain-specific antibodies. We found that mice with increased levels of cross-reactive influenza antibodies also had more IgM antibodies specific for self-antigens. Although the increase in autoreactive IgM antibodies was transient, it correlated with increased susceptibility to disease in mouse models of multiple sclerosis and Guillian-Barre Syndrome. Together, our results suggest that influenza cross-reactive antibodies have the potential to be autoreactive. These data have important implications for developing universal influenza vaccines designed to generate durable influenza cross-reactive antibodies.
A high throughput genetic screen to uncover novel antiviral mechanisms of the interferon system
Authors: Chattopadhyay Saurabh , Subramanian Gayatri , Glanz Anna , Chawla Karan , Gartl Julie , Jay Bryanna 
Published: January 2023

Abstract
The innate immune responses provide the first line of host defense against virus infection. Type I interferon (IFN) system is a well-known mediator of the host innate antiviral responses. Virus infection is recognized by the cellular sensors, also known as pattern recognition receptors, which via a series of signaling pathways, induce the synthesis of IFNs and the IFN-stimulated genes (ISGs). The ISG-encoded protein products function as viral restriction factors, either by interfering with the stages of viral life cycle or by promoting cell death. We have shown that the IRF3, a key transcription factor responsible for inducing IFNs and ISGs, also provides antiviral responses by triggering apoptosis of the infected cells (Chattopadhyay et al Immunity, 2016). To investigate how the IRF3-inducible genes provide antiviral protection, we performed a high throughput genetic screen of human ISGs. Using an shRNA library of the human ISGs, we have identified a novel antiviral ISG, tudor domain containing 7 (TDRD7). TDRD7 inhibits virus replication by interfering with the cellular autophagy pathway, which is required for the replication a number of viruses. Mechanistically, TDRD7 inhibits the autophagy-initiating kinase, AMPK to suppress virus-induced autophagy pathway. We reported that multiple paramyxoviruses, including the clinically relevant human pathogens, respiratory syncytial virus (RSV) and human parainfluenza virus (HPIV3), are inhibited by the new antiviral mechanism of TDRD7 (Subramanian et al PLOS Pathogens, 2018). Using additional RNA and DNA viruses, which activate autophagy during infection, we are investigating whether the new antiviral mechanism similarly inhibits them.
Cell type-specific sensing of murine cytomegalovirus through MyD88 and STING control virus infection
Authors: Piersma Sytse J , Poursine-Laurent Jennifer , Yang Liping , Parikh Bijal A , Yokoyama Wayne M 
Published: January 2023

Abstract
Viruses are sensed by pathogen recognition receptors expressed in the cytosol and on plasma membranes. While toll-like receptors (TLRs) are expressed on membranes and signal through the adapter molecules MyD88 and TRIF, other pathogen-associated molecular patterns are recognized by the DNA sensor cGAS that signals through STING. Murine cytomegalovirus (MCMV) has been reported to stimulate the TLR-MyD88 and cGASSTING pathways, but it is unclear as to what extent both pathways intersect and contribute to viral control. Herein we analyzed survival, viral titers, IFN-I and NK cell responses in mice deficient in MyD88, STING or both. Mice deficient in both MyD88 and STING showed increased mortality and viral titers compared to deficiency in either alone. Bone marrow chimera studies indicate that both hematological and non-hematological compartments contribute to STING-mediated viral control, whereas previously published data indicate that MyD88 does not play a role in the non-hematological compartment. Consistent with these data, our in vitro results showed that stromal cells produce IFN-I in a cGAS-STING-dependent, but MyD88-TRIF-independent manner. Finally, we observed that MCMV-induced natural killer cytotoxicity was partially dependent on both MyD88 and STING-dependent pathways. Taken together, our results indicate that both TLR-Myd88 and cGAS-STING-dependent sensing of MCMV represent partially evolutionary redundant pathways to control virus infection.
The Epigenetic Profile of CD8+ T Cells During SIV Infection
Authors: Pillay Santhoshan T , Nag Mukta , Fogle Jonathan E , De Paris Kristina 
Published: January 2023

Abstract
CD8+ T cells are crucial in the control of HIV infection. Chronic HIV infection results in CD8+ T cell dysfunction that is manifested in reduced cytokine production (IL-2, IFN-g, or TNF-a) and/or reduced cytotoxic function.
We investigated whether epigenetic changes in CD8 T cells contribute to impaired effector mechanisms using the infant Rhesus Macaque model of SIV infection. Epigenetic changes (e.g. DNA methylation) alter the accessibility of promoter regions, thereby regulating gene expression. We analyzed the DNA methylation of the granzyme B, IL-2, IFN-g, and TNF-a promoters of matched PBMCs prior to and 12 weeks post SIV infection (n=4) and of CD8 T cells from lymph nodes (LN) (n=4) and the intestine (n=4). Bisulfite reduced DNA was analyzed by MiSeq Paired End 2×150 sequencing, and the percent methylation at classic CpG sites and at all sites was determined using Qiagen CLC Genome Workbench v.11 software. SIV-negative and -positive samples were compared applying Fisher’s Exact Test (p £ 0.05).
PBMCs (p = 7.77 × 10−16), LNs (p = 0.01) and intestinal (p = 3.33 × 10−16) CD8+ T cells of SIV-infected animals exhibited increased methylation at the promoter for TNF-a. The methylation of CpG sites within the IFN-g (p = 1.11 × 10−16) and granzyme B (p = 8.88 × 10−16) promoters was only increased in LN CD8+ T cells, but not in the intestine or in PBMC. Our results suggest that immune dysfunction during SIV infection can be partially attributed to methylation changes in immune cells. Further, detailed studies of multiple epigenetic changes in larger animal cohorts are needed to explore SIV-induced tissue-, cell-, and gene-specific epigenetic modifications.
Activation of microglia in CD8 T cell-initiated blood-brain barrier disruption induced during Theiler’s virus infection
Authors: Khadka Roman , Zheng Jiaying , Ayasoufi Katayoun , Jin Fang , Trtiz Zachariah , Wu LongJun , Johnson Aaron 
Published: January 2023

Abstract
Immune-mediated blood brain barrier (BBB) disruption is a prominent feature of various neurological conditions for which an emerging role of CD8 T cells is being realized. Our laboratory has developed a model of CD8 T cell-mediated BBB disruption which employs a variation of the Theiler’s murine encephalomyelitis virus (TMEV) infection. At seven days post TMEV infection, the majority of antiviral CD8 T cells recognize an immunodominant virus peptide, VP2121–130, in the context of the H-2Db class I molecule. Upon intravenous administration of this VP2 peptide at seven days post infection, Db:VP2121–130 epitope specific CD8 T cells induce BBB in a perforin dependent process. In this model, we addressed the role of microglia in tandem with CD8+ T cells. Using real time two-photon in vivo imaging, we demonstrate that microglia adopt distinct morphological features including enlarged cell body and fewer ramified processes as early as 6 hours post administration of VP2 peptide. Notably, perforin-deficient mice failed to display BBB disruption and had significantly diminished microglial expression of MHC-II and CD68 in this model. This study demonstrates CD8 T cell promote microglia activation through a perforin-dependent process during BBB disruption. Importantly, microglia are activated concurrently with the onset of vascular permeability and could serve as a critical cell type in this process.
Butyrophilin molecules govern γδ T cell reactivity against phosphoantigens
Authors: Rigau Marc , Ostrouska Simone , Fulford Tom , Johnson Darryl Neil , Woods Katherine , Ruan Zheng , McWilliam Hamish , Hudson Christopher , Tutuka Candani , Wheatley Adam K , Kent Stephen J , Villadangos Jose A , Pal Bhupinder , Kurts Christian , Simmonds Jason , Pelzing Matthias , Hammet Andrew D , Verhagen Anne M , Vairo Gino , Maraskovsky Eugene , Panousis Con , Gherardin Nicholas Anthony , Cebon Jonathan , Godfrey Dale Ian , Behren Andreas , Uldrich Adam Peter 
Published: January 2023

Abstract
Humans have a minor lymphocyte population of gamma-delta (γδ) T cells. The majority of these express a recombined Vγ9Vδ2 T cell receptor (TCR) attractive to immunotherapy. This distinct TCR conveys reactivity to phosphorylated antigens (pAg) that derive from pathogens or accumulate inside tumour cells. Such T cell responses are regulated by butyrophilin (BTN) 3A1 and other membrane-related proteins present on antigen-presenting cells. However, the activation mechanism and direct molecular ligand recognised by the γδ TCR remain a crucial unresolved question. Herein, we used pAg-reactive TCR probes in a whole-genome screen to identify BTN2A1 as an essential ligand. In further investigation, we elucidated its functionality working in cis with BTN3A1. Also, a mutational analysis unveiled critical regions of the γδ TCR are positioned at opposite sides. We locate germ-line encoded residues of the Vγ9 chain were responsible for BTN2A1 binding, whereas two amino-acids of the Vδ2 chain were necessary for a complete response to pAg. In conclusion, we propose a dual-ligand complex model that senses pAg to evoke immune responses, wherein BTN2A1 sets the framework to develop new opportunities on γδ T cell-based immunotherapies.