bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immunological perturbations induced by ongoing blood-stage infection during Plasmodium GAP (Genetically Attenuated Parasites) vaccination
Authors: Patel Hardik , Minkah Nana K. , Sheikh Amina A. , Reynolds Laura , Vaughan Ashley M. , Kappe Stefan H.I. 
Published: February 2023

Abstract
Plasmodium sporozoites (SPZ) are transmitted by mosquito bite, infect the liver, grow and differentiate as intrahepatocytic liver stages (LS) and ultimately form the first generation of red blood cell-infectious merozoites, which initiate the symptomatic blood stage infection. Immunization with replication-deficient radiation attenuated SPZ vaccine has shown to confer sterilizing immunity in animal models by preventing parasite growth into the liver before onset of symptomatic blood stage infection. This attenuated SPZ vaccine has undergone clinical testing and it was observed that sterilizing immunity was achieved high in malaria naïve subjects but lower in malaria pre-exposed subjects residing in malaria-endemic regions. Previous studies in rodent models indicate that the ongoing blood stage infection suppresses protection after immunization with replication deficient irradiated SPZ. We have shown that replication competent late liver stage arresting genetically attenuated parasites (RC-GAP) immunization confer superior protection when compared to irradiated SPZ. However, whether the blood stage infection would also affect the RC-GAP parasite vaccine mediated protective immunity by altering specific immune responses remains unknown. Here, we show that ongoing homologous blood stage infection during Plasmodium yoelii RC-GAP immunization suppress the vaccine mediated immunity in Balb/c mice. Our data suggest that the reduction in protection was associated with the perturbations of long-lived Ag specific antibody as well as tissue resident memory CD8 T cell (TRMs) responses generated against pre-erythrocytic SPZ and LS stages.
Roles of Fc receptor γ chain in inducing protective immune responses after F virus-like particles prime and FI-RSV boost against respiratory syncytial virus infection
Authors: Hwang Hye Suk , Kang Sang-Moo 
Published: February 2023

Abstract
The roles of Fc receptor (FcR) in protection or in inflammatory disease after RSV vaccination and infection remain unknown. Virus-like particles containing RSV fusion proteins (RSV F-VLPs) induce T-helper type 1 antibody responses and protection against RSV. Heterologous RSV F VLP prime and inactivated RSV (FI-RSV) boost vaccination was reported to be effective in providing protection without inflammatory disease. Here we investigated whether the FcRγ chain is important for immune protection by heterologous F VLP and FI-RSV vaccination using FcRγ chain knockout (−/−) mouse model. RSV F-VLP prime and FI-RSV boosted FcRγ−/− mice were not well protected, as shown by higher lung viral titers upon RSV virus challenge compared to RSV F-VLP prime-immunized wild-type mice. RSV F-VLP and FI-RSV immunization of FcRγ−/− mice induced significantly lower levels of neutralizing activity and interferon γ-producing CD8 T cells in bronchoalveolar lavage cells than those in in wild-type mice. In addition, FcRγ−/− mice displayed a trend of enhancing lung histopathology after RSV vaccination and infection. This study suggests that the FcR γ chain plays an important role in antiviral protection and CD8 T cell responses in RSV F-VLP and FI-RSV vaccination after RSV infections.
Resident Memory CD8+ T cells in the respiratory tract prevent transmission of respiratory viruses
Authors: Uddback Ida Elin Maria , Mattingly Cameron , Thomas Jeronay , Kost Kirsten Nicole , Li Zheng-Rong Tiger , Thomsen Allan R , Scharer Christopher D. , Christensen Jan Pravsgaard , Kohlmeier Jacob E 
Published: February 2023

Abstract
Tissue-resident memory CD8+ T cells (TRM) in the respiratory tract reduce viral replication and limit pathology following respiratory virus infections. In infection with heterosubtypic influenza viruses, where pre-existing antibodies does not proved sterilizing immunity, TRM are critical for protection. However, in addition to protecting the host against disease vaccine programs are also designed to limit viral spread in a population. Due to the lack of an animal model to study the effect of TRM on transmission through longitudinal tracking, and with immunological parameters easily identified and manipulated available, this hasn’t been studied before. To solve these issues, we used a luciferase expressing Sendai virus, a natural mouse parainfluenza virus that readily transmits via the aerosol and contact routes, as well as a recombinant influenza virus expressing the immunodominant Sendai NP324-332/Kb epitope to generate SenNP+ memory CD8+ T cells. By utilizing IVIS imaging to non-invasively measure Sendai virus infection over time, we found that mice with pre-existing SenNP+ TRM in the respiratory system don’t transmit Sendai virus to naïve mice when co-housed. In contrast, mice with pre-existing circulating SenNP+ effector memory CD8+ T cells, but no TRM, failed to prevent transmission of Sendai virus to naïve mice when co-housed. In addition, we found that the prevention of transmission was dependent on the production of IFNγ. These findings demonstrates notably that antigen specific lung TRM contributes to herd immunity by preventing respiratory virus transmission. This underscores the importance, and potential, of TRMs generated by vaccines for protection against respiratory viruses.
Systematic examination of antigen-specific recall T cell responses to SARS-CoV-2 versus influenza virus reveals distinct inflammatory profile
Authors: Law Jaclyn C , Koh Wan Hon , Budylowski Patrick , Lin Jonah , Yue FengYun , Abe Kento T , Rathod Bhavisha , Girard Melanie , Li Zhijie , Rini James M , Mubareka Samira , McGeer Allison , Chan Adrienne K , Gingras Anne-Claude , Watts Tania H , Ostrowski Mario A 
Published: February 2023

Abstract
There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. In this study, we investigated human T cell recall responses to fully glycosylated spike trimer, recombinant N protein, as well as to S, N, M, and E peptide pools in the early convalescent phase and compared them with influenza-specific memory responses from the same donors. All subjects showed SARS-CoV-2–specific T cell responses to at least one Ag. Both SARS-CoV-2–specific and influenza-specific CD4+ T cell responses were predominantly of the central memory phenotype; however SARS-CoV-2–specific CD4+ T cells exhibited a lower IFN-γ to TNF ratio compared with influenza-specific memory responses from the same donors, independent of disease severity. SARS-CoV-2–specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. We observed granzyme B+/IFN-γ+, CD4+, and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ T cell responses predominating over CD8+ T cell responses. Peripheral T follicular helper (pTfh) responses to S or N strongly correlated with serum neutralization assays as well as receptor binding domain–specific IgA; however, the frequency of pTfh responses to SARS CoV-2 was lower than the frequency of pTfh responses to influenza virus. Overall, T cell responses to SARS-CoV-2 are robust; however, CD4+ Th1 responses predominate over CD8+ T cell responses, have a more inflammatory profile, and have a weaker pTfh response than the response to influenza virus within the same donors, potentially contributing to COVID-19 disease. Work is in progress to assess long-term T cell immunity 6 months to 1 year after SARS-CoV-2 infection.
The ATP-Exporting Hemichannel Pannexin-1 Promotes CD8+ T Cell Memory Establishment
Authors: Vardam-Kaur Trupti , Peng Changwei , Wanhainen Kelsey , Jameson Stephen C , Silva Henrique Borges da 
Published: February 2023

Abstract
Release of extracellular ATP (eATP) by dying cells is often identified as a "danger signal" by immune cells. However, eATP export by healthy cells is common, and a major transmembrane ATP exporter is the Pannexin 1 (Panx1) molecule. CD8+ T cells express Panx1 during thymic development, at steady-state and during immune response. However, the role of Panx1 on CD8+ T cell-mediated immune response is not well defined. Here, we used genetic and pharmacological ablation tools to address this question. T cell-specific Panx1 deletion does not affect CD8+ T cell thymic development or effector responses to viral infection (LCMV). In contrast, memory CD8+ T cell establishment is impaired by either pharmacological inhibition or CD8-specific Panx1 deletion. Using a tamoxifen-controlled, conditional Panx1 knockout LCMV-specific (P14) CD8+ T cell system, we found that both memory CD8+ T cell generation and survival rely on Panx1. In vitro data further supports these findings: two Panx1 inhibitors, 10Panx and Probenecid, reduce the expression of the central memory marker CD62L. Panx1-deficient CD8+ T cells develop a memory-like phenotype in response to IL-15, but fail to engage mitochondrial respiration and present decreased mitochondrial membrane potential, suggesting Panx1 promotes optimal mitochondrial function. These defects are partially reverted with exogenous eATP. Collectively, our data indicates that cell-intrinsic Panx1-mediated eATP export favors memory CD8+ T cell differentiation. We are currently testing whether CD8-intrinsic Panx1 controls memory CD8+ T cell generation solely as an autocrine eATP source, or if Panx1 also serves as a “rheostat” controlling intracellular ATP levels in antigen-responding CD8+ T cells.
Impacts of vitamin A deficiency on mucosal immunity to respiratory syncytial virus infection
Authors: Hong Suyeon , McGill Jodi L 
Published: February 2023

Abstract
Human respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract disease in infants and young children worldwide. Vitamin A (VA) deficiency (VAD) is one of the most prevalent nutrition-related health problems globally. Acute childhood infections have been linked to an increased risk of VAD, while conversely, VAD leads to increased susceptibility to severe respiratory infections. To date, however, the impact of VAD on RSV infection specifically, or on adaptive immune responses in the respiratory tract, remains unexplored. Here, we used the BALB/c mouse model to determine the impact of VAD on RSV infection and lung virus-specific CD8 T cell immunity. Groups of VA sufficient (VAS) and VAD mice were infected with RSV strain A2. On day 8 after infection, antigen-specific CD8 T cell responses were evaluated using tetramer and intracellular cytokine staining and ELISA assays for IFNγ secretion in cell supernatants. Although no changes in morbidity and mortality were observed between groups, CD8 T cells from VAD animals showed significantly impaired production of IFNγ, suggesting changes in the Th1 balance of the lungs in the context of VAD. Future experiments will focus on changes in the innate and adaptive immune systems in the lungs during VAD and downstream effects on the response to RSV infection.
Defects in the CD8+ T cell response to arthritogenic alphaviruses
Authors: Bullock Christopher B , Davenport Bennett J , Morrison Thomas E , Miller Mark J , Diamond Michael S 
Published: February 2023

Abstract
Arthritogenic alphaviruses have infected millions of people globally. Following acute infection, symptoms of joint pain, swelling, and stiffness can last for months or even years, likely due to persistence of viral RNA and antigen, which also is seen in mice. Intriguingly, wild-type and CD8−/− mice show a similar lack of clearance of viral RNA. Despite this, a mechanism for this CD8+ T cell evasion has not been identified. We hypothesized that there are defects in the generation, function, and migration of the CD8+ T cells after infection with Ross River virus (RRV), a prototype, arthritogenic alphavirus. To study the antigen-specific response, we used a genetically modified RRV expressing the lymphocytic choriomeningitis virus (LCMV)-derived gp33 peptide. Compared to LCMV infection, in which CD8+ T cells are required for viral clearance, RRV infection generates fewer gp33-specific CD8+ T cells in the spleen and draining lymph node, especially at early times after infection. Antigen-specific CD8+ T cells from the draining lymph node at 5 days after RRV infection express much less granzyme B than in LCMV-infected mice. In vivo cytolysis assays showed a qualitative difference in CD8+ T cell killing of targets especially when variant peptides were used for pulsing. Finally, intravital imaging revealed that while both RRV and LCMV infection recruit CD8+ T cells and retain them in an antigen specific manner near infected cells, CD8+ T cells appear to have less contact with RRV than LCMV-infected cells. Identification of a specific defect in the CD8+ T cell response to arthritogenic alphaviruses would increase our understanding of viral immune evasion and provide a target for therapy of these debilitating infections.
Endothelial immune surveillance by intravascular antigen-experienced CD8+ T cells as a novel mechanism of antiviral adaptive immunity
Authors: Barreiro Olga , Loughhead Scott M , Pallis Paris , Eljalby Mahmoud , Zwijnenburg Ton , Collado Victor , Ziegler Carly , Yosef Nir , Shalek Alex , Gerlach Carmen , von Andrian Ulrich H 
Published: February 2023

Abstract
Following acute infection, pathogen-specific CD8+ T cells proliferate and divide in a heterogeneous manner, giving rise to effector and memory T cells with distinct migratory patterns. This migratory division of labor ensures that the host is efficiently scanned for ongoing or recurring infections. Recent evidence suggests that the presumed migratory behavior of the classical effector memory T cell subset needs revision. Here, we report that terminally differentiated effector and effector memory T cells adhere to and patrol the endothelium, while less differentiated T cells migrate into peripheral tissues. Interestingly, patrolling T cells have been observed at vascular beds such as the dermal microvasculature, where they concentrate in arterioles and preferentially migrate against the blood flow. Patrolling T cells survey the endothelium in the search for cognate antigen and, once encountered, cease their migration and establish long-lived interactions with peptide-presenting endothelial cells without inducing cytotoxicity. Finally, single-cell RNA-Seq analysis of patrolling CD8+ T effector cells and blockade experiments to prevent patrolling have unveiled a key and unexpected role for patrolling in the generation and maintenance of the intravascular CD8+ CX3CR1high KLRG-1+ effector memory T cell subset, which in turn is relevant for long-term protective immunity.
Disease-specific antigen presentation on MHC class II is inhibited by a small molecule in Sjögren’s Syndrome
Authors: Gupta Shivai , Nguyen Cuong Q 
Published: February 2023

Abstract
Sjogren’s Syndrome (SjS) is one of the more common autoimmune diseases that has a strong genetic linkage. To date, no vaccine or therapeutic exists to cure SjS, and patients must rely on lifelong therapies to treat symptoms. Class II MHC are the primary susceptibility loci that form the genetic basis for many auto-immune disorders including SjS. I-Ag7 is the MHC in NOD mice that is used for the presentation of autoantigens and plays a critical role in the adaptive immune response. HLA-DQ8 the MHC in humans, is analogous to I-Ag7, in the NOD mouse model and is an important model for the onset of SjS. Using an in-silico molecular docking program a chemical library was screened that defined small molecules that were capable of occupying specific structural pockets along the I-Ag7 binding groove, with the objective of influencing auto-antigen peptide presentation to T cells. In this study we show, that the small molecule TATD can inhibit TCR signaling based on the structural pocket targeting mechanism. TATD previously proven to inhibit the onset of diabetes by blocking the auto-antigen presentation on I-Ag7, was analyzed to observe effects of prevention of SjS by, preventing the accumulation of B and T cells within the salivary gland of NOD mice. Treated mice also showed reduction in the incidence of inflammatory cell infiltration into lacrimal and salivary glands as compared to control mice with notable reduction in of the hallmark SjS anti-nuclear antibodies of Ro52, Ro60 and La. As a result this study presents a novel method for identifying small molecules capable of inhibiting T cell responses, with potentially therapeutic applications.
A cell-free antigen processing system reveals antigenic factors critical for HIV-1 epitope dominance and informs vaccine design
Authors: Sengupta Srona , Reed Madison , Yu Jeanna , Boronina Tatiana , Yang Weiming , Timmons Andrew , Hoh Rebecca , Deeks Steve , Cole Robert N. , Siliciano Janet , Siliciano Robert , Sadegh-Nasseri Scheherazade 
Published: February 2023

Abstract
Certain CD4+T cell epitopes have been associated with immune control of HIV-1 replication and the presence of anti-Env neutralizing antibodies. However, it remains unclear what antigen-dependent factors influence the dominance of certain epitopes in HIV-1 proteins. To study HIV-1 epitope dominance, we used a cell-free antigen processing system previously developed by our group that utilizes soluble HLA-DR1*01:01 (DR1), HLA-DM (DM), protein antigen and three cathepsins in a reducing and low pH environment to allow for antigen binding and cleavage. We subjected HIV-1 antigens from Gag, Pol, Env and accessory proteins Vif, Nef, Tat, and Rev to this system. Immunoprecipitation of pMHC-II complexes followed by peptide elution and identification via LC-MS/MS revealed a map of DR1-bound epitopes across the near-full length HIV-1 proteome. Most identified epitopes were DM-resistant, and in some cases, DM narrowed the epitope diversity to one species. Importantly, we identified 28 novel epitopes, including several glycopeptides eluted from DR1. We noted epitope “hot spots” in HIV-1 antigens and striking similarities in epitopes from HIV polyproteins (Gag precursor) versus individual subunits (Gag capsid). Analysis of the location of several epitopes from smaller HIV-1 proteins based on their known crystal structures mapped to regions of low protein stability and higher solvent accessibility. Finally, we found that several epitopes induced memory CD4+T cell responses in persons living with HIV-1. Thus, by using a minimalist in vitro processing system, we can interrogate novel HIV-1 epitopes and understand how DM-resistance and antigen structure influence epitope dominance, which has important implications for vaccine design.
Akkermansia muciniphila induces Th17 cells by mediating tryptophan metabolism and exacerbates experimental autoimmune encephalomyelitis (EAE)
Authors: Lin Xun , Tawch Suzanne , Singh Ankita , Morgun Andriy , Shulzhenko Natalia , Kumar Pawan 
Published: February 2023

Abstract
Multiple sclerosis patients have been shown to have increased Akkermansia muciniphila (Akk) colonization. However, the role of Akk to regulate MS remains poorly understood.
Here, we utilized fecal microbiota transplantation (FMT) model and generated Akk+ and Akk− SPF C57BL/6 mice. When subjected to EAE, Akk+ mice displayed worse clinical scores. An increase of spinal cord infiltrating IL-17A-producing and GM-CSF-producing CD4+ T cells was observed in Akk+ mice at 15 days post EAE induction. Moreover, ileum explant culture showed an elevated IL-17A production in Akk+ mice. Furthermore, we found dysregulated tryptophan in the cecal contents of naïve Akk+ mice. Additionally, using Kovac’s reagent, Akk was confirmed to utilize tryptophan and produce indole, an aryl hydrocarbon receptor (AhR) ligand. AhR activation has previously been shown to promote Th17 differentiation. Therefore, we performed Th17 differentiation in vitro. The treatment of Akk-derived tryptophan metabolites significantly induced IL-17A response. CH-223191, an AhR antagonist, abrogated the induction of Akk-mediated Th17 differentiation, suggesting that Akk-mediated Th17 differentiation was dependent on AhR. In addition, increased AhR agonists were observed in the feces of MOG immunized Akk+ mice as compared to Akk− mice.
In conclusion, our data showed that Akk exacerbated EAE possibly by tryptophan-dependent induction of IL-17A-producing CD4+ T cells.
Interleukin-17A deficient mice microbiota induced regulatory T cells and suppressed experimental autoimmune encephalomyelitis (EAE) in WT HLA-DR3 transgenic mice
Authors: Shahi Shailesh K , Jensen Samantha N. , Ghimire Sudeep , Carter CheyAnne Q. , Guseva Natalya V. , Gibson-Corley Katherine , Bossler Aaron D. , Ganesan Sukirth M. , Karandikar Nitin J. , Mangalam Ashutosh K. 
Published: February 2023

Abstract
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and among all the genes associated with MS, HLA class II genes have the highest relative risk. Although IL-17A is thought to be a major cytokine in the pathogenesis of MS, the exact role of IL-17A in the MS is still poorly understood. Specifically, it is unclear whether IL-17A is required for disease initiation or disease severity or in both. Therefore, in the present study, utilizing HLA-DR3 transgenic mice lacking IL-17A (HLA-DR3.IL-17A−/−), we investigated the importance of IL-17A in disease development and progression in experimental autoimmune encephalomnyelitis (EAE) an animal model of MS. We observed that HLA-DR3.IL-17A−/− mice had a higher frequency of CD4+CD25+FoxP3+ regulatory T cells (Treg)s and developed milder EAE compared to IL-17 sufficient HLA-DR3 mice. Further characterization of mechanism identified a novel role of IL-17A in regulating the disease progression through modulation of immunoregulatory responses. We also identified an important role of gut microbiota in IL-17A dependent disease regulation specifically depletion of gut bacteria with ability to promote Treg population in IL-17A sufficient HLA-DR3 mice. Fecal transplantation of HLA.DR3 mice with HLA-DR3. IL17A−/− showed milder EAE and an increase in Treg cells in HLA-DR3 mice confirming a role of gut microbiota in shaping Treg repertoire and function. Additionally, we observed higher frequency of metabolic pathway involved with Treg promoting short chain fatty acid (SCFA) metabolism in HLA-DR3.IL17A−/− mice. Thus our study shows a novel role of IL-17A in immune homeostasis and inflammation by regulating levels of Tregs through modulation of gut microbiota.