bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effect of GITR on lung effector T cell subpopulations during influenza infection
Authors: Chu Kuan Lun , Batista Nathalia V , Watts Tania H 
Published: January 2023

Abstract
Influenza remains an important global threat. Tissue resident memory T cells (Trm) are critical in protection against influenza, and it is important to identify key mechanisms regulating their formation and persistence. GITR, an NF-κB activating TNFR family member, is required on CD8 T cells for maximal responses against influenza. Our recent work (Mucosal Immunology, doi:10.1038/s41385-018-0105-5) provided evidence that GITRL on monocyte-derived inflammatory APCs provides crucial signals through GITR on T cells in the lung tissue (termed Signal 4), allowing effector T cell accumulation and optimal Trm formation during influenza infection in mice. During influenza infection, responding lung T cells are heterogeneous, some will give rise to terminally differentiated effector cells, while others will become Trm. It remains unknown how GITR affects these subpopulations. To address this issue, we characterized these CD8 T cell subsets using markers Ly6C, KLRG1, T-bet, and the chemokine receptor CX3CR1. By staining with Ly6C and CX3CR1, we identified three different CD8 T cell subsets with differential expression of Ly6C and CX3CR1 (Ly6ChiCX3CR1 hi, Ly6ChiCX3CR1 lo, Ly6CloCX3CR1 lo). Ly6ChiCX3CR1 hi CD8 T cell subset likely represents the most terminally differentiated effector cells as they have the highest expression of KLRG1 and T-bet. Using the adoptive transfer of transgenic OT-I cells, we discovered that there is a larger loss of the Ly6CloCX3CR1 loCD8 T cell in the absence of GITR when compared to the other two subsets. We are currently investigating which of the three subsets give rise to the lung Trm population after influenza infection and the timing and nature of the GITR-dependent signals involved.
Funded by CIHR:FDN143250
Plasmacytoid dendritic cells contribute to HIV diseases and viral persistence via IDO-dependent mechanisms
Authors: Li Guangming , Ma Jianping , Yu Haisheng , Bi Wenwen , Wu Yaxu , Cheng Liang , Su Lishan 
Published: January 2023

Abstract
The combination antiretroviral therapy (cART) effectively suppresses HIV replication and enables HIV-infected individuals to live long-productive lives. However, the persistence of HIV reservoir cells with latent or lowreplicating HIV in patients under cART make HIV infection an incurable disease. Plasmacytoid dendritic cells (pDCs) suppress HIV replication through secreting type I interferon (IFN-I). We have reported that pDCs play a major pathogenic role in chronic HIV infection in vivo. In this study, we discovered that pDCs-depletion during cART completely resolved HIV immune pathogenesis and rescued anti-HIV T cell response in humanized mice. Importantly, HIV reservoirs (total cell-associated HIV DNA as well as cells with replication-competent HIV virus) are reduced by pDCs-depletion. We showed that HIV infection induced IDO expression in monocytes and DC via pDC-dependent mechanism. Interestingly, IDO inhibition during cART similarly resolved HIV immune pathogenesis and rescued anti-HIV T cell response, correlated with reduced HIV reservoirs in humanized mice in vivo. Finally, we proved that pDCs depletion and IDO inhibition acted through the same pathway to reverse HIV pathogenesis. We conclude that pDCs persistently activated by HIV lead to IDO expression that induces host immune exhaustion, contributing to HIV reservoirs persistence during effective cART. Strategies to disrupt the pDC-IDO axis will provide novel opportunities to achieve HIV-1 functional cure therapy.
Δ42PD-1 enhances HIV replication and suppresses maturation of dendritic cells
Authors: Zhou Runhong , Mo Yufei , Zhou Dongyan , Chen Zhiwei 
Published: January 2023

Abstract
Previously, we discovered a new PD-1 isoform, which consists of a 42-base pairs loss from the start of exon 2 that is equivalent to a 14 amino acid in-frame deletion. Therefore, we named this new PD-1 isoform as Δ42PD-1. Here, we found that Δ42PD-1 was highly expressed on monocyte-derived dendritic cell (MoDC) in healthy donors, while significantly decreased in HIV patients with or without antiretroviral therapy. Consistently, in vitro assay, HIV infection suppressed Δ42PD-1 expression in total MoDCs. However, upregulation of Δ42PD-1 was observed in mature MoDC (high CD83+CD86+) after HIV infection, although the mature MoDC population was unraised, which consistent with previous report that HIV infection do not mature MoDC. Therefore, to investigate the role of Δ42PD-1 on HIV replication, Δ42PD-1 positive and negative MoDC were sorted out by FACS and infected with R5-tropic HIV (JR-CSF) respectively. Interestingly, Δ42PD-1 positive MoDC was higher susceptible to HIV than Δ42PD-1 negative MoDC. Maturation is important for dendritic cell to perform innate and adaptive immune response. Further investigation revealed that Δ42PD-1 negative MoDC had higher maturation level than Δ42PD-1 positive MoDC after LPS stimulation, which means that Δ42PD-1 may suppress DC maturation. So far, we conclude that Δ42PD-1 not only enhances HIV replication, but also suppresses dendritic cell maturation. It warrants to further study the role of Δ42PD-1 on DC-mediated immune responses during HIV infection in vivo.
Not just acute: IRF-7 plays a key role in restriction of chronic gammaherpesvirus infection
Authors: Johnson Kaitlin E , Jondle Christopher Ned , Lange Philip T , Aurubin Carlie A , Tarakanova Vera L 
Published: January 2023

Abstract
Gammaherpesviruses (GHVs) are ubiquitous pathogens that establish lifelong infections and are associated with a variety of malignancies, including lymphomas. While risk factors for these virus-driven cancers are poorly understood, it is clear that increased reactivation of these viruses from latency contributes to viral oncogenesis.
Therefore, it is important to identify host factors that restrict GHV reactivation. Interferon regulatory factor 7(IRF-7) is one of two transcription factors that are primarily responsible for driving type I interferon (IFN) expression and subsequent innate immune responses. Unlike previous studies which have focused on IRF-7 in the context of acute viral infections, we found that GHV reactivation is increased in chronically infected IRF-7−/− mice. Interestingly, the virus-specific T cell response that is typically critical for control of viral reactivation during chronic infection was not decreased in IRF-7−/− mice. However, we observed a decrease in expression of select IFN induced genes (ISGs) in IRF-7−/− GHV-infected mice. Importantly, these differentially affected ISGs have been shown to inhibit GHV replication. Ongoing studies will determine the contribution of IRF- 7 to the expression of IFN, ISGs, and IFN-dependent antiviral activity in the context of chronic GHV infection. Importantly, successful completion of these studies will provide insight into how the host innate immune system controls chronic GHV infections and viral pathogenesis.
Investigating the immunological role of galectin-9 on natural killer (NK) cells in human immunodeficiency virus (HIV)
Authors: Motamedi Melika , Elahi Shokrollah 
Published: January 2023

Abstract
NK cells play an integral role in mediating immune responses to viral infections; however, their function is compromised during chronic diseases such as HIV, partly due to an increase expression of inhibitory receptors. Thus, the reduced immune responses elicited by NK cells in HIV can be the result of the engagement of inhibitory immune checkpoint molecules with their respective ligands. Galectin-9 (Gal-9) is a tandem-repeat type galectin that possess a wide range of immunomodulatory properties such as interacting with Tim-3, which is upregulated on T cells during chronic conditions. Previously, our group has shown that interaction of Gal-9 on regulatory T cells with Tim-3 on CD8+T cells, renders these T cells more permissible to immunosuppression and subsequently leads to their exhaustion. We aimed to further study the role of Gal-9 on NK cell function in HIV patients. As a comparison, we also analyzed another inhibitory receptor known as TIGIT. Our preliminary data indicates upregulation of surface Gal-9 on NK cells in HIV infected individuals when compared to healthy controls. We observed two effector NK cell populations with dichotomous functionality. TIGIT+NK cells expressed more cytotoxic molecules (GzmB and perforin) and less IFNγ. Conversely, Gal-9+NK cells expressed less cytotoxic molecules, but more IFNγ. Additionally, Gal-9+NK cells, in contrast to Gal-9−NK cells, co-express negligible amounts of GzmB and perforin, which is detrimental to their cytotoxic abilities. We believe that understanding the underlying biochemical pathway associated with Gal-9+NK cell dysfunction can pave the way for potential therapeutic strategies.
The Ly49G2 inhibitory receptor is essential to MHC I-dependent NK cell control of murine cytomegalovirus infection
Authors: Cronk John Michael , Gamache Awndre , Gillespie Alyssa , Brown Michael G 
Published: January 2023

Abstract
Licensed Ly49G2+NK cells mediate H-2Dk-dependent control of murine cytomegalovirus (MCMV) in NK gene complex (NKC)C57L mice. However, a precise role for the Ly49G2 inhibitory receptor in Dk-dependent MCMV control is not defined. Thus, we generated Ly49g2C57L mutant mice via CRISPR/Cas9 gene-editing. A single cytosine insertion resulted in Ly49G2 truncation and undetectable NK cell surface expression. Ly49G2null mice exhibited increased mortality due to abrogated MCMV control by NK cells, despite an otherwise unmodified Ly49 repertoire and normal NK cell development. We further found Dk-dependent MCMV control requires Ly49R signaling, as blocking the activation receptor prior to infection resulted in rapid MCMV spread. Coincident with MCMV control, Ly49R+Ly49G2+ (R+G2+) NK cells were more frequently Klrg1hi, CD27−CD11b+, and CD62Llo than their Ly49R+ (R+) counterparts, and this effect was Dk-dependent. R+G2+ NK cells likewise out proliferated R+ NK cells in infected Ly49G2wt mice. NK cell subset activation and proliferation differences suggested impaired virus control in Ly49G2null mice might result from inept target cell sensing or poor NK cell expansion. To verify a role for Dk-licensed NK cells, we examined donor NK cells after adoptive transfer to NK cell-deficient hosts. Licensed R+G2+ NK cells in peripheral blood and spleen robustly expanded and mediated MCMV control in contrast to R+ NK cells. Both Ly49G2 and Ly49R receptors expressed together in NK cells thus are essential to Dk-dependent MCMV control. Our data and novel mouse model suggest licensed NK cells may be better equipped to sense infected targets, which aligns with human genetics studies implicating a role for licensed NK cells in control of chronic infection.
LAG-3 modulation of natural killer cell immunoregulatory function
Authors: Ali Ayad , Moran Michael T , Tuazon Jasmine , Gyurova Ivayla , Vignali Dario AA , Waggoner Stephen N 
Published: January 2023

Abstract
Natural killer (NK) cells suppress antiviral immunity by killing a fraction of virus-specific CD4 T cells. This occurs during the first 3 days of infection, is perforin-dependent, and coincides with NK-cell localization in the splenic white pulp. While the receptors governing this NK-cell activity are ill-defined, it is clear that negative feedback mechanisms must exist to prevent excessive pruning of T-cell responses. Comparative transcriptome analysis of red pulp and white pulp localized NK-cells derived from late in the window of immunoregulatory activity (day 3) reveals increased expression of Lag3 in white pulp NK-cells. LAG-3 is an inhibitory receptor that binds peptide-bound major histocompatibility complex II (pMHC-II). We find a progressive increase in LAG-3 protein expression on NK-cells with time post-infection and localization to the white pulp. Consistent with its putative inhibitory role, antibody-mediated neutralization of LAG-3 enhances NK-cell killing capacity in vitro. Preliminary analysis reveals reduced virus-specific T cells in mice lacking Lag3 in NK-cells (Ncr1Cre+Lag3fl/fl) relative to control mice. We hypothesize that LAG-3 upregulation on NK-cells confers inhibitory feedback signals from surrounding MHC-II+ cells to terminate NK-cell suppression of T cells. Uncovering the role of LAG-3 in NK cell immunoregulatory function will provide a novel target to constrain this suppression and enhance vaccine-elicited T cell responses.
Latency III gene products of Epstein-Barr Virus (EBV) are associated with Systemic Lupus Erythematosus (SLE) genetic risk loci
Authors: Laurynenka Viktoryia , Chen Xiaoting , Carter Martha , Parameswaran Sreeja , Eswar Shruti , Kaufman Kenneth M. , Namjou Bahram , Weirauch Matthew T. , Kottyan Leah C. , Harley John B. 
Published: January 2023

Abstract
SLE affects millions with increasing diagnostic prevalence. Genetic studies have identified &gt;600 mostly regulatory variant associations. EBV has been nominated as a causal factor for SLE from immunochemistry and epidemiologic studies. EBNA2 concentrates at SLE risk loci (Nat Genet 50:699 2018) suggesting mechanisms. Additional evidence supporting EBV as an SLE origin would advance this hypothesis of etiology.
Previous simulation using our RELI algorithm revealed an astonishing association with Epstein-Barr virus nuclear antigen 2 (EBNA2) (OR=5.96, Pc=E-25) (Nat Genet 50:699, 2018). The &gt;100 risk alleles associated at p&lt;5E-8 for SLE were curated and reduced to 83 loci by linkage disequilibrium pruning. We evaluated the available 53 virally encoded and 13,051 human TF ChIP-seq (chromatin immunoprecipitation with DNA sequencing) datasets. In addition to EBNA2 (now OR=3.7, Pc=1.96E-18 after Bonferroni correction), two of the 53 viral TF data sets, EBNA3C and EBNALP, each of which are EBV Latency III gene products, were also strongly associated with the SLE risk loci (OR=6.0, Pc=4.19E-18; and OR=3.3, Pc=5.53E-18). Moreover, among the human TF datasets strongly associated with SLE risk loci (Pc&lt;E-6), those from EBV infected and transformed B cells are highly concentrated (OR≈56, P&lt;E-100) and, in addition, the human TFs that are known to form super-enhancers upon B cell transformation by EBV (e.g., NFκB subunits) also tend to be concentrated at the SLE risk loci (OR&gt;30, p&lt;E-25). Meanwhile, genetic associations for depression, anxiety, and schizophrenia show no such relationships.
These new results further the possible validity of the hypothesis that SLE is originally caused by the Latency III expression program of EBV.
The Effect of Dietary Fiber Intake on Systemic Lupus Erythematosus (SLE) Disease in NZB/W Lupus Mice
Authors: Panther Eric James , Ren Jingjing , Cabana-Puig Xavier , Abdelhamid Leila , Swartwout Brianna , Luo Xin M. , Reilly Christopher M. 
Published: January 2023

Abstract
Dysbiosis in the gut microbiota has been observed in a various autoimmune disease, including SLE, which could cause a leaky gut, triggering an immune response, and thus worsening autoimmune disease expression. In our current studies, we hypothesized that increasing dietary fiber would create a healthy microbiota environment in the gut, leading to decreased leakiness of the gut and to decreased disease expression in and NZB/NZW female mice. NZB/NZW mice were placed on standardized high fiber (HF 30%) or low fiber (LF 0.4%) for 12 weeks beginning at 10 weeks of age. Mice were assessed as they aged for various parameters of disease including proteinuria and anti-dsDNA antibody production. Alteration of the microbiota and short chain fatty acid levels were also assessed. At 36 weeks-of-age, the mice were euthanized and we assessed occlusion protein expression, splenocyte profiles, and kidney tissue. We found as the mice aged, their body weights, anti-dsDNA antibody levels, and proteinuria were not significantly different between the groups. Similarly, there were no differences in SCFA levels. In regard to the microbiota, Chlostridiales bacteria were consistently increased in the HF treated mice compared to the LF treated mice. In regard to disease progression, spleen weight, immune cell profiles, proteinuria, dsDNA levels, and kidney pathology, there was no difference between the HF and LF treated groups. Taken together, these results indicate that in the NZB/W female mouse, a HF diet may alter the microbiota but does not influence disease progression.
Single-cell RNA sequencing of pancreatic islets reveals the complexity of autoimmune diabetes throughout its initiation and development
Authors: Zakharov Pavel , Hu Hao , Wan Xiaoxiao , Unanue Emil R 
Published: January 2023

Abstract
Type one diabetes (T1D) is a spontaneous autoimmune disease that results in pancreatic islet beta-cell death driven by diverse immune cells. However, molecular signatures of the leukocyte populations in T1D remain poorly defined. Here, using single-cell transcriptional analysis, we examined intra-islet leukocytes at various stages of disease: from its very early start, through its control phase and finally to the final effector stage. Early stages before clinical diagnosis are not accessible for human studies.
We found that both CD4 and CD8 T cells showed heterogeneity at the initial stage of autoimmune inflammation and already contained effector cells. Moreover, the disease progression at all times was accompanied by regulatory sets establishing control mechanisms. In line with that, we also detected accumulation of anergic and exhaustion-associated phenotypes over time. Analysis of the islet macrophages showed substantial divergence, including novel population with anti-inflammatory and dead-cell clearance features. Autoimmune process resulted in polarization of islet macrophage into terminal pathogenic state via two-step activation program. While stage 1 marked by NF-kB activation was present in non-diabetic condition, stage 2 was inflammation-induced and had additional IFN-gamma activation. Interestingly, the final effector stages were not dominated by CD8 cytotoxic T cells but by pro-inflammatory macrophages.
Overall, our analysis comprehensively describes stages of T1D on the basis of lymphoid and myeloid transcriptional activation programs, providing a detailed single-cell atlas of autoimmune diabetes initiation and development. Our findings will guide future studies in staging human T1D.
Characterization and use of human insulin transgenic mouse models for type 1 diabetes
Authors: Amdare Nitin Purushottam , Shultz Leonard D , Greiner Dale L , DiLorenzo Teresa P 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is characterized by T cell-mediated islet-specific autoimmunity leading to β cell destruction and loss of insulin production. Insulin is the primary antigen produced by β cells and due to incomplete conservation between the mouse and human insulin genes, some of the important disease-relevant T cell epitopes can be missed in the widely studied non-obese diabetic (NOD) mouse model. Thus, considering the limitations of NOD mice, we generated a novel NOD mouse model transgenically expressing human insulin (NOD.hIns mice) under the control of the human promoter. Female NOD.hIns mice spontaneously developed autoimmune diabetes as early as 15 weeks (incidence 62% by 30 weeks of age, n=21) vs NOD mice (41%, n=24), accompanied by numerous hallmarks of human T1D (including thymic human insulin expression and variable degrees of pancreatic islet infiltration by immune cells). Next, we cultured islet-infiltrating CD8 T cells from NOD.hIns mice and tested them for recognition of peptides unique to human preproinsulin. These efforts uncovered at least three T cell epitopes, validating that human insulin is a target of the autoimmune response in NOD.hIns mice. This concept was confirmed using T cells derived from NOD.hIns mice deficient in both murine insulin genes (NOD.Ins1ko.Ins2ko.hIns mice). NOD.hIns mice expressing human class I MHC molecules associated with T1D (HLA-A*24:02 and B*39:06) are currently being studied. Such well-characterized, and highly human-relevant, T1D models can be used to develop robust immune monitoring tools and to test and refine antigen-specific therapeutic strategies for T1D.
Follicular helper T cells express a metabolic and cell signaling gene signature in a lupus-prone murine model
Authors: Gong Minghao , Cornaby Caleb , Michailidis George , Morel Laurence 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive follicular helper T (Tfh) cells license high-affinity autoantibody production. Strikingly, the frequency of circulating Tfh is correlated with disease activity in SLE patients. As such, understanding the molecular mechanisms responsible for the aberrant Tfh cell generation and activation in lupus is of fundamental significance. We previously demonstrated that expanded Tfh cells in the B6.Sle1.Sle2.Sle3 (TC for triple congenic) lupus model exhibit high glycolysis and oxidative metabolism, which can be constrained by inhibiting glycolysis with 2-deoxyglucose (2DG). We performed RNA-seq analyses of splenic Tfh and naïve CD4+ T cells (Tn) comparing between TC and B6 mice. First, data revealed a large number of shared gene signatures in Tfh and Tn comparing between TC and B6 group, implicating that the aberrant development of Tfh initiates as early as Tn state. Further alignment of the Tfh transcriptome obtained from RNA-seq and earlier microarray assays demonstrated concerted alterations in numerous gene signatures of overactivation of T cells including dysregulated tyrosine kinase signaling and MAPK signaling pathways. Gene set enrichment analyses (GSEA) further revealed altered metabolic pathways (e.g., oxidative phosphorylation and pyruvate metabolism) among splenic TC Tfh cells. Finally, we demonstrated that 2-DG partially correct the aberrant expression patterns in TC splenic Tfh cells, restoring oxidative phosphorylation and the MAPK pathways. Since 2DG eliminates the expansion of autoreactive TFh cells, these results suggest that these two pathways may be critical to lupus Tfh cell function.
T cell cooperation in the induction of autoimmunity in a murine model of multiple sclerosis
Authors: Garza Celeste , Joern Rachel Robinson , Rojano Elba Mirelle , Forsthuber Thomas 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a T cell-driven autoimmune disease. There are many unknowns regarding the disease etiology and pathogenesis. Importantly, the mechanisms of peripheral tolerance and dysregulation of pathogenic mechanisms are poorly understood. It is known that patients with MS exhibit myelin reactive T cells in the blood; however healthy controls also show myelin reactive T cells in the blood. Additionally, T cells from patients with MS react to many different myelin peptides. Current human studies do not support that patients exhibit large populations of T cells specific for a single myelin-antigen responsible for the induction of autoimmune pathology. In contrast, a quorum of several low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides. We found that disease in the experimental autoimmune encephalomyelitis (EAE) model of MS can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. These results support the hypothesis that a quorum of autoreactive T cells could suffice to initiate autoimmune disease. We have developed a system whereby T cells of different antigen specificities can be traced in order to track the dynamics and kinetics of those T cells in disease initiation and progression. The results of this study provide further insights into the dynamic interactions between T cells of different antigen specificities.