bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-intrinsic B7-H1 in melanoma and ovarian cancer regulates mTOR, autophagy and tumor growth
Authors: Clark Curtis A , Gupta Harshita B. , Pandeswara Srilakshmi , Sareddy Gangadhara R. , Yuan Bin , Hurez Vincent , Li Rong , Vadlamudi Ratna , Curiel Tyler J 
Published: January 2023

Abstract
Tumor B7-H1 (PD-L1) promotes tumor immune evasion by interaction with T cell PD-1. B16 melanoma and ID8agg ovarian cancer express B7-H1. We genetically made B7-H1lo or B7-H1hi lines to study additional B7-H1 effects. Control B16 and ID8agg grew more rapidly in vitro versus B7-H1lo cells and B7-H1hi B16 cells grew faster than control. In vivo, B16 and ID8agg grew faster than B7-H1lo lines in immunodeficient NSG mice. B16 challenge in NSG mice with B7-H1hi cells produced more lung metastases versus parental, which produced more metastases than B7-H1lo. αB7-H1 significantly reduced tumor growth and metastases. These data support an immune-independent role for tumor B7-H1 in tumor growth and metastatic spread. Control B16 and ID8agg cells had elevated TORC1 and reduced TORC2 versus B7-H1lo cells. The mTOR inhibitor rapamycin reduced cell growth greater in parental versus B7-H1lo cells in vitro. Also in line with reduced TORC1, B7-H1lo cells had increased autophagy (LC3-II/actin ratio and autophagosome formation) compared to parental cells. Notably, autophagy inhibitors chloroquine and 3-methyladenine had a greater inhibitory effect on in vitro proliferation of control B16 versus B7-H1lo cells. Inhibition of autophagy in vivo with either agent significantly reduced tumor growth of B16 but not B7-H1lo cells, suggesting that B7-H1 replete tumors are more dependent on the stress-modulating function of autophagy versus B7-H1lo tumors. Our studies show novel tumor-intrinsic B7-H1 signal effects that regulate mTOR and autophagy signals directly associated with immune-independent tumor growth, supporting a paradigm shifting concept that tumor B7-H1 augments stress response and metabolism through cell-intrinsic mechanisms.
Musocal vaccine for universal influenza A protection
Authors: Phillips Joy A , Tallapaka Shailendra B , Vetro Joseph A , Sanderson Sam D , Thoman Marilyn L 
Published: January 2023

Abstract
The rapid mutation rate of the influenza virus requires that the yearly flu vaccine development cycle start months in advance of the flu season. The search for a single vaccine able to protect against multiple strains of influenza has thus long been the Holy Grail of flu vaccine research. Such a vaccine would require an antigenic target that is highly or completely homologous among all influenza subtypes. There is one such conserved region present on the otherwise highly variable influenza A hemagglutinin protein. This short, linear peptide sequence known as the fusion peptide is highly conserved among influenza A viral subtypes. Up until now, the difficulty generating strong immune responses against short peptide epitopes has prevented exploitation of this conserved region as a vaccine target. We previously developed a novel peptide adjuvant termed EP67 that induces mucosal and systemic adaptive immune responses to conjoined peptide sequences. In this study, we conjugated EP67 to the conserved influenza A fusion peptide sequence. The resulting peptide conjugate was then encapsulated in biodegradable PLGA 50:50 nanoparticles, and the nanoparticle vaccines were delivered to either the lungs or the nasal mucosal tissue. Preliminary testing shows that intranasal administration of our encapsulated peptide vaccine protects young mice from lethal infection with either H1N1 or H3N2 strains of influenza. Aged animals are also protected from lethal infection using this nanoparticle vaccine. These studies support the continued exploration mucosal nanoparticle vaccines containing conserved influenza sequences as a promising strategy for universal influenza protection.
Use of biologic nanolipoprotein particles containing monophosphoryl lipid A as a novel intranasal vaccine platform for Bacillus anthracis
Authors: Weilhammer Dina R , Dunkle Alexis D , Blanchette Craig , Boone Tyler , Gilmore Sean , Corzett Michele , Fischer Nicholas , Lehmann Doerte , Lychak Cheri , Hoeprich Paul , Driks Adam , Rasley Amy 
Published: January 2023

Abstract
There is considerable interest in developing a novel Bacillus anthracis vaccine that improves upon the shortcomings of the licensed vaccine for broader, more rapid protection of the population. Ideally, a vaccine would recognize the spore in addition to having anti-toxin effects as well as induce robust mucosal and lung-associated immunity for early recognition and clearance. Here, we investigate nanolipoprotein particles (NLPs) containing the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) as a platform for intranasal vaccination against Bacillus anthracis. Modified lipids enabled attachment of disparate spore and toxin protein antigens. Intranasal vaccination of mice with B. anthracis antigen-MPLA-NLP constructs vs. delivery with free MPLA induced robust IgG and IgA responses in serum and in bronchoalveolar and nasal lavage. Typically, a single dose sufficed to induce sustained antibody titers over time. Robust T cell responses to various spore antigens were also detected in the lung. When multiple immunizations were required, specific antibodies were detected earlier in the boost schedule with MPLA-NLP-mediated delivery than with free MPLA. Administering combinations of constructs induced robust responses to all incorporated antigens, indicating potential for a multivalent vaccine preparation. Experiments to determine the efficacy of multivalent vaccine preparations against inhalational B. anthracis challenge are ongoing. In summary, the NLP platform enhances humoral, cellular and mucosal responses to intranasal immunization, indicating promise for NLPs as a flexible, robust vaccine platform against B. anthracis and potentially other inhalational pathogens.
Immune history to influenza infection and vaccination predicts antibody responses to the seasonal influenza vaccine
Authors: Hertz Tomer , Shagal Ayelet , Ohmit Suzanne , Monto Arnold S 
Published: January 2023

Abstract
Vaccination, the most cost-effective public health intervention, stimulates the immune system to generate protective memory responses. A variety of factors impact an individual’s heterogeneity in vaccine induced immune responses, such as age and gender and ‘immunological history’ - the individual’s memory antibody repertoire to previously encountered pathogens and vaccines. Immune history is particularly interesting in influenza since humans are constantly infected and vaccinated annually. To profile the effect of immune history to previously influenza infections, we used samples form an influenza vaccine efficacy trial (FluVacs) in adults aged 18–65 conducted in 2007–2008. Samples were collected at baseline d0, post vaccination d21 and at the end of the season d90. We used antigen microarrays spotted with overlapping 20mer peptides from the HA and NA proteins of the seasonal vaccine to generate antibody profiles at baseline to represent individuals’ immune history. Profiles were also generated post-vaccination. We used unsupervised clustering to cluster profiles of individuals at baseline. We found that individuals clustered into several distinct antibody profiles. Importantly, we found that most individuals within the same baseline clusters produced similar antibody profiles post vaccination. We also compared the pre- to post-vaccination profiles and found that overall the vaccine generated a relatively modest boost of the previous antibody repertoire. Overall our results highlight the importance of profiling immune history to previous influenza infections as a baseline measurement that may be predictive of vaccine induced immune responses and vaccine-induced protection.
An innate helping hand for B cells on the margin during chronic viral infection
Authors: Cranert Stacey A , Moran Michael T , Waggoner Stephen N 
Published: January 2023

Abstract
Marginal zone (MZ) B cells are an anatomically segregated population well-positioned to respond to blood borne pathogens and implicated in defense against encapsulated bacteria. MZ B cells are also an important source of the anti-inflammatory cytokine, IL-10. As such, these cells are poised to prevent secondary bacterial infection or immune pathology during chronic virus infection. Surprisingly, CD169+ MZ macrophages and CD21+CD23neg B cells were lost in mice during persistent clone 13 lymphocytic choriomeningitis virus (LCMV) infection in the absence of natural killer (NK) cells. Confocal staining revealed a near complete absence of the MZ by day 10 of infection in NKdeficient mice, which we previously found contain enhanced populations of antiviral T cells. Intriguingly, depletion of either CD4 or CD8 T cells did not restore the MZ compartment in NKdeficient mice, but combined depletion of both subsets of T cells prevented the loss. This phenomenon was independent of NKT cells. We hypothesize that NK cells play an important role in curtailing harmful inflammation and preventing pathogenic bacterial diseases during chronic viral infection by sustaining the MZ. This discovery has important implications for health, immune function, and viral clearance during persistent infection.
Regulation of effective vs. ineffective B cell responses to chronic viral infections.
Authors: Staupe Ryan P , Wherry E. John 
Published: January 2023

Abstract
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are chronic viral infections that cause significant morbidity and mortality worldwide. Current efforts to vaccinate against these pathogens have been unsuccessful and have failed to induce effective neutralizing antibodies capable of mediating sterilizing immunity. Natural HIV of HCV infection elicits the production of affinity matured class-switched antibodies that target viral proteins. While these antibodies can drive viral evolution, they are ineffective at controlling infection. Moreover, it is now clear that the evolution of these antibody responses, and the B cells that produce them, during chronic infection are radically different than those generated by acute infection or vaccination. Despite these observations, little is known about the underlying mechanisms of B cell differentiation and control of effective antibody production during chronic viral infection. We have developed a novel technique that allows us to track the virus-specific B cell response in the lymphocytic choriomeningitis virus (LCMV) model, a mouse model of chronic viral infection. Using this technique we have found that chronic viral infection does not cause a skewing of the virus-specific B cell response to the plasma cell fate and away from the germinal center fate but induces a robust plasma cell response in an antigen-level and T-cell dependent manner. These results suggest that altered differentiation of virus-specific B cells early during the response to chronic viral infection may contribute to the temporal delay in development of effective neutralizing antibody responses during chronic infection.
Moving in for the kill: natural killer cell migration in regulation of humoral immunity
Authors: Moran Michael T , Rydyznski Carolyn E , Waggoner Stephen N 
Published: January 2023

Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that provide immune defense against pathogens and tumors, and act as potent regulators of adaptive immunity. Notably, NK cells inhibit humoral immunity by restricting the magnitude of follicular helper T-cell (TFH) and germinal center (GC) B-cell responses in a perforin-dependent manner. This suppression occurs at an early stage of infection that coincides with an anatomic redistribution of NK cells within secondary lymphoid organs. Specifically, infection with lymphocytic choriomeningitis virus (LCMV) triggers transient NK-cell redistribution from the vascularized red pulp into the white pulp of the spleen. Many of these NK cells localize at the border between T- and B-cell zones where cognate interactions between TFH and B cells facilitates development of GCs. Some NK cells also penetrate deep into the B-cell follicle. We have investigated this phenomenon using a flow cytometry-based intravascular staining method and through confocal microscopy. We have observed a novel subset of NK cells expressing CXCR5 that coincidentally arise with NK-cell redistribution to spleen regions (i.e. B-cell zone) rich in CXCL13. We hypothesize that this subset of NK cells localize in a CXCR5 dependent manner near cells participating in the early steps of GC formation, including TFH, which allows for NK-cell contact and perforin-dependent killing of GC-inducing cells that ultimately dampens the development of immunity to infection. These regulatory NK cells are an innovative target for clinical strategies aimed at subverting or enhancing humoral immune responses.
LAG-3 expressing antigen-specific CD4+ T cells attenuate lung inflammation during acute influenza virus infection
Authors: Dutta Avijit , Huang Ching-Tai , Chen Tse-Ching , Lin Chun-Yen , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Huang Yu-Lin 
Published: January 2023

Abstract
The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. In our antigen-specific mouse model system for influenza virus infection, influenza hemagglutinin antigen-specific CD4+ T cells responded to acute infection with Th1 effector phenotype. A significant proportion of them were also with concurrent expression of LAG-3, CTLA-4, GITR or CD25. Adoptive transfer of purified LAG-3 expressing hemagglutinin antigen-specific CD4+ T cells controlled lung inflammation with acute influenza virus infection, as represented by the activation of co-transferred influenza hemagglutinin antigen-specific CD8+ T cells. Control of the inflammation by LAG-3 expressing antigen-specific Th1 CD4+ T cells was not necessarily associated with impaired capacity of virus eradication. These results reveal, besides effector function for virus eradication, subsets of CD4+ T cells activated by acute influenza virus infection also acquired regulatory function to attenuate inflammation for reducing the damage to the host. These subsets of CD4+ T cells may be employed as the practical handle for management of severe influenza disease.
Defining limits on efficacy of CD8 T cell-based HIV vaccines
Authors: Ganusov Vitaly V , Yang Yiding 
Published: January 2023

Abstract
It is generally accepted that an effective HIV vaccine should be able to induce neutralizing antibodies and memory CD8 T cells. Yet, basic features of protective CD8 T cell responses remain poorly defined. Using recently published data from a cohort of HIV-infected patients that were followed from the onset of symptoms into the chronic phase, we determined the basic quantitative in vivo features of HIV-specific CD8 T cell responses. First, we found that the number of responses recognizing different viral epitopes (immune response breadth) varied greatly between patients and on average, 8 epitopes were recognized by CD8 T cells. Surprisingly, we found that in most patients the breadth did not change significantly over the course of first year of infection suggesting that most HIV-specific T cell responses were primed in acute infection. There was a strong negative correlation between the predicted precursor frequency and the rate of expansion of epitope-specific T cells suggesting intraclonal competition. Finally, we found that the majority of CD8 T cell populations expanded and contracted in unison; however, about 20% of all CD8 T cell responses had a discordant dynamics suggesting interclonal competition. Taken together, our results suggest that effective control of HIV infection can be achieved with broad CD8 T cell response if vaccine-induced breadth is larger than that induced by a natural infection. However, broader T cell response will likely lead to interclonal competition between responses, and boosting the magnitude of epitope-specific T cell responses may reduce the expansion rate of these responses due to intraclonal competition. Our results thus suggest potential limits on the efficacy of CD8 T cell-based HIV vaccines.
Myelin-specific CD8+ T cells exacerbate CNS autoimmunity
Authors: Wagner Catriona , Goverman Joan 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although the pathogenic pathways of MS are not fully understood, myelin-specific T cells are hypothesized to initiate disease. Myelin-specific CD4+ T cells have been the main focus of MS research and animal models of MS have relied exclusively on the activity of CD4+ T cells. However, a substantial body of data from MS patients indicate that CD8+ T cells are also involved in MS pathogenesis. We hypothesized that recruitment of myelin-specific CD8+ T cells to the site of inflammation initiated by CD4+ T cells could influence disease. To test our hypothesis, we use a mouse model of MS, experimental autoimmune encephalomyelitis (EAE) in which adoptive transfer of CD4+ T cells specific for myelin oligodendrocyte glycoprotein (MOG) induces CNS autoimmunity. To determine the influence of CD8+ T cells, we introduce CD8+ T cells from a TCR-transgenic mouse model expressing a TCR specific for a MHC class I-restricted epitope of myelin basic protein (MBP) into the periphery of mice just after disease induction. We found that the recruitment of the MBP-specific but not control CD8+ T cells exacerbated CD4+ T cell-initiated EAE. Furthermore, recruitment of MBP-specific CD8+ T cells increases the number of MOG-specific CD4+ T cells within the CNS at peak disease. Interestingly, mice that received MBP-specific CD8+ T cells exhibited an increase in symptoms associated with brain inflammation. These data suggest that the interplay between CD4+ and CD8+ T cells specific for two different myelin proteins is critical for determining the manifestation of CNS autoimmune disease.
Th17 cell differentiation increases aquaporin-3 expression, which is further increased by treatment with NaCl.
Authors: Zhou Xiaoming , Nurmukhambetova Saule , Kim Yong-Chan , Adair Patrick , Wu Chuan , Scott David W , Kuchroo Vijay K , Lees Jason R 
Published: January 2023

Abstract
Aquaporin3 (AQP3) is one of 13 members of the aquaglyceroporin family that transports water and other small molecules across the cell membrane. In the immune system, AQP3 is important in macrophage phagocytosis, T cell migration, and dendritic cell activation. Th17 cells are thought to play a pivotal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), which is sensitive to salt intake. Through microarray, we previously demonstrated that in vitro differentiation of mouse Th17 cells increases AQP3 mRNA abundance over that seen in Th0 T cells. Utilizing both Western and flow cytometric analyses, we now show that this mRNA increase is correlated with an increase in AQP3 protein abundance, whereas Th1 differentiation has no significant effect on AQP3 protein abundance as compared with Th0 cells. Moreover, increased concentration of NaCl (40 mM over standard) to the medium further augments AQP3 protein abundance, but only within Th17 differentiated cells. We have also extended these studies to human T cells and found that human CCR6 positive cells, previously characterized as IL-17 producing cells constitutively express more AQP3 protein than human CCR6 negative cells. To test whether Th17 cells express more AQP3 protein than Th1 cells in vivo, we induced EAE by immunization of the mice with MOG35–55 with the mice injected with PBS as a control. We analyzed AQP3 protein abundance in splenic T cells directly ex vivo with flow cytometry and found that Th17 cells express more AQP3 protein than Th1 cells under both conditions. We conclude that Th17 cells express more AQP3 than Th1 cells both in vitro and in vivo, and that treatment with NaCl in vitro further increases AQP3 protein abundance only in Th17 cells. Supported by NMMS PP3448.
Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation
Authors: Ji Woo Seong , Jang Hyun-Young , Lee Sang-Il , Lee Sang-Myeong , Park Byung-Hyun 
Published: January 2023

Abstract

Objective
The type III histone deacetylase SIRT1 is an enzyme critical in the modulation of immune and inflammatory responses. However, data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mice.

Methods
CIA was induced in mSIRT1 KO and wild-type (WT) mice. Arthritis severity was gauged by clinical, radiographic, and pathologic scores. Levels of cytokines and transcription factors were determined by real-time RT-PCR and ELISA. Flow cytometry was used to quantify T cells and dendritic cells (DCs). T cell response was also investigated when co-cultured with antigen-pulsed DCs.

Results
Compared with WT counterparts, arthritis in mSIRT1 KO mice was less severe and proved less destructive to joints. Expression levels of inflammatory cytokines, matrix metalloproteinases, and ROR-γT in mSIRT1 KO mice were also reduced by comparison, paralleled by reductions in Th1 and Th17 cells and CD80- or CD86-positive DCs. In addition, impaired maturation of DCs and resultant declines in Th1/Th17 immune response were observed in mSIRT1 KO mice. In co-culture, DCs of mSIRT1 KO mice were less adept at driving T cell proliferation and Th1/Th17 immune response.

Conclusion
Myeloid cell-specific deletion of SIRT1 appears to suppress CIA through modulation of DC maturation. Thus, careful investigation of DC-specific SIRT1 downregulation is needed to weigh the therapeutic utility of agents targeting SIRT1 in RA.
CD70 methylation of a regulatory region increases with age in lupus patients.
Authors: Ray Donna , Harlow Sioban , Strickland Faith , Orlowski Rachel , Marder Wendy , McCune W. Joseph , Somers Emily C 
Published: January 2023

Abstract
T cell DNA hypomethylation contributes to systemic lupus erythematosus (SLE), although the mechanisms are poorly understood. Previous work has shown that CD70, a B cell costimulatory ligand, is hypomethylated and overexpressed in lupus T cells, and that the overexpression leads to increased B cell costimulation and concomitant immunoglobulin overproduction. Recent evidence suggests that the methylation status of certain genes may characterize ‘epigenetic aging’, and that epigenetic age may be a stronger predictor than chronological age of health outcomes. CD70 has not been examined in this context, therefore we sought to characterize the methylation status of CD70 in lupus patients across age. CD4+ T cells were obtained from peripheral blood of 89 consecutive lupus patients enrolled in a population-based cohort. CD70 methylation of a regulatory region was assessed by bisulfite conversion and pyrosequencing. Mean methylation across 10 sites known to be hypomethylated in lupus patients was measured and correlated with age. CD70 methylation increased linearly with increasing age of lupus patients. These results suggest that CD70 may be involved in “epigenetic aging”, and that the increased hypomethylation of CD70 in younger patients may contribute to the earlier onset and increased severity of disease. Further studies of aging effects on methylation of immune genes involved in lupus may improve our understanding of the variability in susceptibility and onset of the disease.