bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the epigenetic programming underlying CD8 T cell dysfunction in solid tumors
Authors: Philip Mary , Fairchild Lauren , Sun Liping , Viale Agnes , Leslie Christina , Schietinger Andrea 
Published: January 2023

Abstract
Tumor-specific CD8 T cells in progressive solid tumors express inhibitory receptors and fail to proliferate and produce effector cytokines. Using a mouse model (ASTxCre-ERT2) in which tamoxifen (TAM) treatment induces an oncogenic driver neoantigen, SV40 large T antigen (Tag) in hepatocytes, we previously showed that tumor-specific CD8 T cells (TCRSV40-I) become unresponsive quite early during the pre-/early malignant phase. While the dysfunctional state is initially plastic, TCRSV40-I cells soon enter a fixed dysfunctional state with the phenotypic, functional, and molecular hallmarks of T cells from late-stage human tumors. To define the epigenetic programs associated with plasticity and imprinting of tumor-specific T cell dysfunction, we used the “Assay for Transposase-Accessible Chromatin using Sequencing” (ATAC-Seq) to map chromatin accessibility in TCRSV40-I cells isolated from pre/early malignant lesions as well as in TCRSV40-I differentiating to the normal effector and memory states. Chromatin accessibility changes underlying TCRSV40-I activation and differentiation in pre-malignant lesions diverged from that in normal differentiation, and we observed 2 distinct chromatin accessibility patterns in dysfunctional TCRSV40-I correlating with the plastic and fixed dysfunctional states. Surprisingly, memory TCRSV40-I transferred into mice with late-stage established Tag-expressing hepatocellular carcinomas displayed these same 2 chromatin accessibility profiles, thus regardless of the initial CD8 T cell epigenetic state, epigenetic remodeling drives tumor-specific T cell differentiation to the dysfunctional state in both pre-malignant lesions and late established solid tumors.
Identification of flu-specific ICOS+CD38+ cTfh after influenza vaccination
Authors: Muselman Alexander D , Herati Ramin Sedaghat , Vella Laura , Su Laura , Tebas Pablo , Wherry E. John 
Published: January 2023

Abstract
The foundation of successful vaccines lies in the ability to prime the immune system to target a specific pathogen. The interaction between follicular helper T cells (Tfh) and B cells within germinal centers is necessary for the production of class-switched, affinity-matured antibodies. However, the size, diversity, and specificity of the T cell receptor (TCR) repertoire of the Tfh during an immune response remains unknown. We identified a subset of circulating Tfh (cTfh) coexpressing ICOS and CD38 that expresses markers of recent activation, such as the proliferation marker Ki67 and the transcription factor Helios. This activated cTfh subset increases following influenza vaccination. To begin to interrogate how the TCR repertoire changes in human cTfh cells responding to a vaccine, we performed T-cell receptor beta chain sequencing on cTfh from individuals before and after influenza vaccination. Although the ICOS−CD38− cTfh maintained a stable TCR repertoire pre- and 7 days post vaccination, the ICOS+CD38+ cTfh exhibited increased clonality indicative of antigen-driven activation and expansion. Using HLA class II HA306- and HA40-specific tetramer staining on peripheral blood from HLA-DR0401 individuals, we then further assessed the specificity of the responding cTfh at day 7 after vaccination. We found many tetramer-positive cells that expressed ICOS and CD38 in the cTfh subset, confirming that the ICOS+CD38+ response after vaccination contains influenza-specific cells. Ultimately, rational vaccine design will depend on better understanding of the clonotypic response elicited in response to various pathogens and their relevance to the overall immune response.
A computationally designed hemagglutinin stem-binding protein provides in vivo protection from influenza in the ferret model.
Authors: Brichacek Allison , Treants Merika , Hartman Amy , Reed Douglas , Baker David , Fuller Deborah Heydenburg , Cole Kelly Stefano 
Published: January 2023

Abstract
Influenza viruses cause thousands of deaths worldwide and remain a prominent public health issue. Currently, the influenza vaccine is the best tool available at protecting against infection, but the correct strains are hard to predict and the vaccines do not always work. More effective antiviral drugs are needed. Protection against influenza by broadly neutralizing antibodies targeted to a highly conserved region in the hemagglutinin (HA) stem shows great potential for immunotherapy. We have investigated the protective efficacy of an engineered protein, HB36.6, that was computationally designed to bind with high affinity to the same region in the HA stem as targeted by broadly neutralizing antibodies. Studies in the mouse model demonstrated that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza, both when administered as a single dose of 6.0 mg/kg up to 48 hrs prior to challenge and significantly reduces disease when administered as a daily therapeutic after challenge. The current study was designed to evaluate HB36.6 in the ferret model, comparing prophylactic and therapeutic efficacy of this new antiviral against high dose influenza aerosol challenge. Similar to data obtained in the mouse model, results from these studies demonstrated significant reduction in viral load and clinical signs of disease in ferrets treated with HB36.6 compared to untreated controls or ferrets treated with Tamiflu. Together, these results show that binding of HB36.6 to the influenza HA stem region alone was sufficient to reduce the viral infection and disease process in vivo. These studies demonstrate a potential new class of antivirals for influenza.
Lactococcus lactis expressing HIV antigens on a Group A Streptococcus (GAS) pilus serves as potential dual mucosal vaccine against HIV and GAS
Authors: Jones Andrew , Chamcha Venkateswarlu , Quigley Bernard , Scott June , Amara Rama Rao 
Published: January 2023

Abstract
Due to the majority of HIV/SIV transmissions occurring via the mucosal route, a mucosal vaccine that generates immune responses along the genitorectal tract may provide the tools needed to combat HIV/SIV in its earliest stages of infection. We recently demonstrated that an orally delivered mucosal vaccine based around the probiotic bacterium Lactococcus lactis expressing HIV/SIV antigens fused to a cell wall anchored Group A Streptococcus (GAS) pilus induces a strong systemic and mucosal immunity in mice. To test the mechanisms behind immunogenicity, we gavaged mice and examined the activation level of various dendritic cells in the intestinal Peyer’s patches and found increased activation of CD11b+CD8− DC compared to wild-type L. lactis, indicating some inherent adjuvant activity of the GAS pilus. As there is evidence that GAS pilus specific antibodies may aid in the protection from GAS infection, we evaluated the ability of our L. lactis vectors to generate these pilus-targeting antibodies. We observed a strong induction of GAS-pilus specific antibodies in both mice and rhesus macaques orally immunized with our L. lactis vectors. We were unable to detect antibody responses generated against the backbone L. lactis bacterium, underlining the immunodominance of the GAS pilus in these vectors. These data suggest that these constructs may serve a dual role in generating protective immune responses against HIV and GAS infections.
Non-specific activation of autoreactive B cells after anthrax vaccination delays protection
Authors: Sawatzki Kaitlin , Ataca Sila , Watanabe Akiko , Kuraoka Masayuki , Walter Emmanuel , Kelsoe Garnett H. , Feng Feng , Kepler Thomas B 
Published: January 2023

Abstract
Anthrax Vaccine Adsorbed (AVA) vaccination protects against anthrax infection by eliciting a neutralizing antibody response. However, protective antibody titers are not observed in human sera until at least three vaccinations have been administered over six months. Even then, humoral responses to AVA do not provide long-term immunity without an annual booster, presenting a serious challenge in public health.
We followed six healthy volunteers over the standard five-dose, 18-month AVA schedule to characterize immunoglobulin genetics during vaccination. Plasmablasts were isolated one week after each vaccination and natively-paired heavy- and light-chain immunoglobulin mRNA were sequenced. Immunoglobulin sequences were analyzed for mutations and clonal evolution.
After primary vaccination, the average mutation frequency of observed plasmablast lineages indicated they were derived from previously affinity matured B cells (6.1–7.7%). Many sequences had very high mutation frequencies (&gt;10%), a characteristic that has been linked to multiple antigen exposures. We synthesized antibodies from these lineages and tested them against a panel of human antigens. While they had little to no affinity to anthrax antigens, they displayed significant affinity to a variety of autoantigens. These memory lineages were non-persistent, and we observed naïve B cell activation after secondary vaccination. We tested antibodies from naïve-derived lineages first observed after secondary vaccination and found these to be anthrax-specific and non-autoreactive. Thus, while primary AVA vaccination elicits a robust memory response, it is non-protective and delays anthrax-specific naïve B cell recruitment until secondary vaccination.
Vaccinated female mice are better protected against Tularemia infection compared to their male counterparts
Authors: Sunagar Raju , Kumar Sudeep , Franz Brian J , Gosselin Edmung J 
Published: January 2023

Abstract
Francisella tularensis (Ft) is a Category A biothreat agent for which there currently is no FDA-approved vaccine. Thus, there is a substantial effort underway to develop an effective tularemia vaccine. While it is well established that gender can significantly impact susceptibility to primary infection, the impact of gender on vaccine efficacy is not well established. Thus, development of a successful vaccine against tularemia will require an understanding of this impact. In this study, a role for gender in vaccine-induced protection against tularemia is identified for the first time. Mucosal vaccination with inactivated Ft (iFt) LVS elicited gender-based protection in C57BL/6 mice against respiratory challenge with Ft LVS. Specifically, vaccinated male mice were more susceptible to subsequent Ft LVS challenge. This increased susceptibility in male mice correlated with increased bacterial burden, tissue inflammation, and elevated proinflammatory cytokine production late in infection. In contrast, improved survival of iFt-vaccinated female mice correlated with reduced bacterial burden and enhanced levels of Ft-specific Abs in serum and broncho-alveolar lavage (BAL) fluid. Furthermore, vaccination with a live attenuated vaccine consisting of an Ft LVS super oxide dismutase (SodB) mutant demonstrated a similar gender bias in protection following Ft SchuS4 challenge. Of particular significance is the fact that these are the first studies to demonstrate that gender differences impact disease outcome in the case of lethal tularemia following mucosal vaccination. In addition, these studies further emphasize the fact that gender differences must be a serious consideration in any future tularemia vaccine development studies
The common human HAQ STING variant affects Pneumovax® 23 efficacy
Authors: Patel Seema , Tucker Heidi , Jin Lei 
Published: January 2023

Abstract
Multiple polysaccharide vaccines have been licensed in U.S including the pneumococcal vaccine Pneumovax® 23, meningococcal vaccine Menomune, and Salmonella typhi vaccine Typhim Vi. Polysaccharides antigens activate the Stimulator of Interferon Gene (STING/MPYS) pathway in B cells. We previously found that ~3% of Caucasian and ~16% of Asian are homozygous for a STING variant containing three non-synonymous SNPs, R71H-G230A-R293Q (HAQ). Here, using human B cells derived from HAQ individuals and a knock-in mouse expressing mouse-equivalent of human HAQ variant, we investigated the impact of the HAQ variant on the effectiveness of Pneumovax® 23. Our results suggest that Pneumovax® 23 is likely less effective in HAQ individuals than the wt (R232) STING carriers. Our novel finding revealed, for the first time, the impact of the common HAQ human STING variant on Pneumovax® 23 efficacy and illustrated the need to develop personalized STING-targeting immunotherapy.
Obesity outweighs antibody responses generated by an aduvanted H7N9 influenza vaccine and fails to protect mice from influenza infection
Authors: Hertz Tomer , Karlsson Erik , Krammer Florian , Schultz-Cherry Stacey 
Published: January 2023

Abstract
Obesity is a risk factor for developing severe influenza infection making vaccination of utmost importance for this high-risk population. Yet, vaccinated obese animals and adults have decreased neutralizing antibody responses. We tested the hypothesis that addition of a squalene-based adjuvant to an influenza H7N9 vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Adjuvanted vaccine increased both neutralizing and non-neutralizing antibody levels as compared to vaccine alone; however, obese mice were not protected from lethal H7N9 challenge. Increasing the antigen dose affords no added protection and decreasing the viral dose did not fully mitigate the increased mortality seen in obese mice. Although obese mice did mount virus-specific antibody responses; both the breadth and the magnitude of the response was decreased as compared to lean mice. Furthermore, antigen microarrays spotted with overlapping 20mer peptides (with 15 overlap) of the hemgaluttinin and neuraminidase H7N9 vaccine strain revealed that lean mice generated stronger and broader antibody responses to the H7 HA and N9. Interestingly, several specific antigens that were targeted in lean mice were not targeted by the obese mice, including some located around the sialic acid recptor binding domain. Overall, these studies highlight that while adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health.
Herpes simplex virus-2 ΔgD vaccination primes robust cellular immunity with memory Th17 cell recall following challenge
Authors: Weiss Kayla A , Petro Christopher , Herold Betsy C. , Jacobs William R. 
Published: January 2023

Abstract
Approximately 25 percent of women are infected with herpes simplex virus (HSV)-2 in the United States. Even with anti-viral treatments, the rate of HSV transmission has increased 30 percent in the last 20 years. Furthermore the risk of acquiring an HIV infection increases 2–4 fold for HSV-2-infected individuals. Therefore, the need to have an FDA-approved HSV vaccine is immediate. Recently we have developed a single-cycle HSV-2 vaccine strain genetically deficient in glycoprotein D (HSV-2 ΔgD). Complete protection from disease and the establishment of latency is observed following either HSV-1 or HSV-2 challenge of HSV-ΔgD-vaccinated mice. We have also previously demonstrated that HSV-2 ΔgD elicits a protective, broadly functional antibody response. We hypothesized that HSV-2 ΔgD vaccination also primed T cell immunity, contributing to vaccine-induced protection. We observe both CD4 and CD8 T cells are activated by vaccination, and contract to establish a stable memory population. Vaccine-induced memory CD8 T cells are polyfunctional cytokine-producers with 55 percent specific for the immunodominant HSV gB498-505 epitope. Memory CD4 T cells primed by vaccination are quickly recalled to the infection site following challenge and exhibit a Th17-dominant phenotype with 60 percent of recalled cells producing IL-17A. We also determined that CD4 T cell help is required to stabilize the germinal center B cell population and to elicit protective antibodies following vaccination. Together, our data demonstrate HSV-2 ΔgD vaccination induces robust cellular, as well as humoral, immunity and likely an ideal vaccine vector.
Redistribution of T follicular helper cells to the lungs of neonatal mice infected with influenza
Authors: Fuller Michael John , Bradley John E. , Randall Troy D 
Published: January 2023

Abstract
The infant immune system responds poorly to both infection and vaccination, however the mechanisms responsible for impaired immune responses in neonates are incompletely understood. Here we analyzed T and B cell responses to influenza infection in neonatal mice. We found that neonatal mice were much more susceptible to primary influenza infection and cleared virus with delayed kinetics. Although CD8 T cell responses were slightly delayed in neonates compared to adults, neonates ultimately generated robust CD8 T cell responses. Following resolution of infection, however, the accumulation of tissue-resident memory (Trm) CD8 T cell responses was impaired in mice infected as neonates. In contrast, the appearance of influenza-specific CD4 T cells, including T follicular helper (Tfh) cells, was not delayed. Surprisingly, Tfh cells appeared in the lungs of neonatal mice, but not the lungs of adult mice. Tfh cells in the lungs of neonates correlated with the appearance of germinal center (GC) B cells and the formation of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs. However, despite the appearance of local Tfh and GC B cells, the production of influenza-specific antibody was severely impaired in neonatal mice. Thus, despite the differentiation of influenza-specific Tfh in both lymphoid organs and lungs of neonatal mice, B cell-mediated immunity was still profoundly impaired. Nevertheless, while mice given a primary influenza infection as neonates had diminished Trm CD8 T cell responses and impaired B cell-mediated immunity, they were able to survive lethal rechallenge as adults, indicating that protective immunity could be generated in neonates.
Virtual memory cells make a major contribution to the response of aged influenza-naive mice to influenza virus infection
Authors: Blackman Marcia A , Lanzer Kathleen G , Cookenham Tres , Reiley William W 
Published: January 2023

Abstract
The ability to mount adaptive immune responses is impaired with age. One important contributing factor is the dramatic decline in repertoire and number of naïve T cells, raising the possibility that the response to new infections relies largely on cross-reactive memory T cells. We have analyzed the CD8 T cell response to influenza virus in influenza-naïve aged mice and confirmed that memory phenotype cells do make a major contribution to the response to new infections. There are two possible origins of the responding memory T cells. The response may be mediated by fortuitously cross reactive memory cells that were generated by earlier heterologous infections, which can be defined as “true memory” (TM). This possibility is supported by the observations that T cell recognition is highly degenerate and many unexpected cross-reactivities have been defined. Alternatively, the response may be mediated by antigen-specific memory cells that have been generated in the absence of antigen exposure, termed “virtual memory” (VM) cells. This possibility is supported by the observation that the ratio of VM:TM increases dramatically with age. To determine whether TM or VM respond to influenza in aged mice we used dual adoptive transfer with VM and TM cells. The data show that the response to influenza virus is dominated by memory CD8 T cells with a VM phenotype. The ability of these cells to afford protective immunity and develop into long-lived memory cells is under investigation and has implications for our understanding of immune function in the aged.
Tissue resident memory CD8 T cells augment innate immunity for tissue-wide antiviral protection
Authors: Zhu Jia , Peng Tao , Chang Yon , Layton Erik , Sun Sijie , Phasouk Khamsone , Johnston Christine , Halford William P , wald Anna , Corey Lawrence 
Published: January 2023

Abstract
Tissue-resident memory (TRM) CD8+ T cells provide effective, localized protection against pathogen re-encountering at barrier surfaces. During human herpes simplex virus 2 (HSV-2) infection, TRM CD8+ T cells persist at dermal-epidermal junction, interacting with basal keratinocytes and performing immune containment. The precise mechanism of how a few TRM CD8+ T cells convey broad tissue-wide protection is unclear. This study investigated the effects of TRM CD8+ T cells on tissue microenvironment by laser microdissecting and transcription profiling keratinocytes during human genital HSV-2 infection. In asymptomatic reactivation and lesion forming recurrences, keratinocytes exhibited a cell-intrinsic antiviral signature. Genes involved in RNA trafficking and protein translation were down-regulated, while a subset of interferon stimulated genes (ISGs) was elevated. The ISG expression was widely spread throughout the epidermis in the affected area. IFN-γ was expressed in TRM CD8+ T cells, but IFN-α and IFN-β were undetectable in keratinocytes and whole tissue. In primary cultured keratinocyte and fibroblast cells, pretreatment of IFN-γ delayed and restricted HSV gene expression at immediate-early stage of viral transcription. The inhibition on viral gene expression was dose-dependent and relied on IFN-γ receptor signaling. Thus, by harnessing cell-intrinsic innate immunity, TRM CD8+ T cells convey a tissue-wide antiviral protection in a non-cytolytic manner.
Accumulation of Th1 biased Tfh in lymphoid tissues during chronic SIV infection defines functionally distinct germinal center Tfh cells
Authors: Velu Vijayakumar , Mylvaganam Geetha H , Gangadhara Sailaja , Iyer Smita S , Hong Jung Joo , Ibegbu Chris , Villinger Francois , Amara Rama Rao 
Published: January 2023

Abstract
Follicular helper CD4T cells (Tfh) play a critical role in determining the magnitude and quality of antibody (Ab) responses. Chronic HIV infection is associated with hypergammaglobulinemia and germinal center Tfh (GC-Tfh) in lymphoid tissue may contribute to this process. However, the heterogeneous nature of GC-Tfh cells and the relative contribution of specific GC-Tfh subsets to viral persistence and Ab production is not understood in HIV/SIV infections. Here, we characterized the phenotype and function of GC-Tfh cells based on the expression of chemokine receptors associated with Th1 (CXCR3), Th2 (CCR4) and Th17 (CCR6) in lymph nodes following SIV251 infection in rhesus macaques (RMs). In SIV naïve RM, only a small fraction of GC-Tfh expressed CXCR3, CCR4 and CCR6. During chronic SIV infection, despite a global depletion of CD4 T cells, there was an increase in total GC-Tfh cells. Interestingly the majority of expanded GC-Tfh cells expressed CXCR3, while the proportion of CCR4+ cells did not change but CCR6+ cells decreased. CXCR3+ but not CXCR3−GC-Tfh produced IFN-g and IL-21 while both expressed CD40L following stimulation. IHC analysis demonstrated an accumulation of IFN-g+ T cells within the follicles during chronic infection. CXCR3+GC-Tfh also expressed higher levels of ICOS, CCR5 and a4b7, contained more copies of SIV DNA compared to CXCR3−GC-Tfh cells. Both CXCR3+ and CXCR3−GC-Tfh delivered help to B cells in vitro, but CXCR3+ GC-Tfh favored the production of IgG and IgG1. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC-Tfh cells, which are phenotypically and functionally distinct from conventional GC-Tfh cells and contribute to IgG1 biased hypergammaglobulinemia and viral reservoirs