bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eosinophil Chemotactic Chemokines (Eotaxin, Eotaxin-2, RANTES, Monocyte Chemoattractant Protein-3 (MCP-3), and MCP-4), and C-C Chemokine Receptor 3 Expression in Bronchial Biopsies from Atopic and Nonatopic (Intrinsic) Asthmatics
Authors: Ying Sun , Meng Qiu , Zeibecoglou Kyriaki , Robinson Douglas S. , Macfarlane Alison , Humbert Marc , Kay A. Barry 
Published: January 2023

AbstractAtopic (AA) and nonatopic (NAA) asthma are characterized by chronic inflammation and local tissue eosinophilia. Many C-C chemokines are potent eosinophil chemoattractants and act predominantly via the CCR3. We examined the expression of eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), MCP-4, and CCR3 in the bronchial mucosa from atopic (AA) and nonatopic (intrinsic; NAA) asthmatics and compared our findings with atopic (AC) and nonatopic nonasthmatic controls (NC). Cryostat sections were processed for immunohistochemistry (IHC), in situ hybridization (ISH), and double IHC/ISH. Compared with AC and NC, the numbers of EG2+ cells and the cells expressing mRNA for eotaxin, eotaxin-2, RANTES, MCP-3, MCP-4, and CCR3 were significantly increased in AA and NAA (p &lt; 0.01). Nonsignificant differences in these variants were observed between AA and NAA and between AC and NC. Significant correlations between the cells expressing eotaxin or CCR3 and EG2+ eosinophils in the bronchial tissue were also observed for both AA (p &lt; 0.01) and NAA (p = 0.01). Moreover, in the total asthmatic group (AA + NAA) there was a significant inverse correlation between the expression of eotaxin and that of the histamine PC20 (p &lt; 0.05). Sequential IHC/ISH showed that cytokeratin+ epithelial cells, CD31+ endothelial cells, and CD68+ macrophages were the major sources of eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4. There was no significantly different distribution of cells expressing mRNA for these chemokines between atopic and nonatopic asthma. These findings suggest that multiple C-C chemokines, acting at least in part via CCR3, contribute to bronchial eosinophilia in both atopic and nonatopic asthma.
Activation of Regulatory Cells Suppresses Experimental Allergic Encephalomyelitis Via Secretion of IL-10
Authors: Stohlman Stephen A. , Pei Liong , Cua Daniel J. , Li Zhihua , Hinton David R. 
Published: January 2023

AbstractSuppression of CD4+ Th1 cell-mediated autoimmune disease via immune deviation is an attractive potential therapeutic approach. CD4+ Th2 T cells specific for myelin basic protein, induced by immunization of young adult male SJL mice, suppress or modify the progression of CNS autoimmune disease. This report demonstrates that activation of non-neuroantigen-specific Th2 cells is sufficient to suppress both clinical and histological experimental allergic encephalomyelitis (EAE). Th2 cells were obtained following immunization of male SJL mice with keyhole limpet hemocyanin. Transfer of these cells did not modify EAE, a model of human multiple sclerosis, in the absence of cognate Ag. Disease suppression was obtained following adoptive transfer and subcutaneous immunization. Suppression was not due to the deletion of myelin basic protein-specific T cells, but resulted from the presence of IL-10 as demonstrated by the inhibition of Th2-mediated EAE suppression via passive transfer with either anti-IL-10 or anti-IL-10R mAb. These data demonstrate that peripheral activation of a CD4+ Th2 population specific for an Ag not expressed in the CNS modifies CNS autoimmune disease via IL-10. These data suggest that either peripheral activation or direct administration of IL-10 may be of benefit in treating Th1-mediated autoimmune diseases.
Allergic responses to human rhinoviruses in a mouse model (128.1)
Authors: McLean Gary R , Bartlett Nathan W , Walton Ross P , Johnston Sebastian L 
Published: January 2023

Abstract
Respiratory virus infections are the major cause of acute exacerbations of asthma with human rhinoviruses (RV) accounting for two thirds of infections. Excessive Th2-type responses and deficient anti-viral Th1-type responses generated against RV are associated with exacerbation severity. We recently reported a mouse model of RV infection and showed primary infection was associated with only Th1 responses, however RV infections are frequent throughout life. In a mouse model of repeated RV infection we show the induction of Th2 immune responses, virus-specific IgE and other hallmarks of an allergic response following secondary RV challenge. Both homologous and heterologous RV serotype rechallenges induced eosinophil and lymphocyte infiltration of bronchoalveolar lavage (BAL) and RV-specific serum IgE. The Th2 cytokine IL-4 was detected in BAL 1 day after secondary RV infection, the eosinophil survival/activation factor IL-5 and the chemotactic factor eotaxin were detected in BAL prior to eosinophil cellular infiltration. These results suggest that a Th2-biased immune response generated following repeated RV infection in vivo could contribute to the pathogenesis of asthma exacerbations. With this model it will be possible to dissect out the molecular mechanisms of Th2-biased immune responses to RV and their role in the pathogenesis of RV-induced acute asthma exacerbations.
γδ T cells and NK cells contribute to resistance to polyomavirus–induced tumors (128.15)
Authors: Mishra Rabinarayan , Chen Alex T , Welsh Raymond M , Szomolanyi-Tsuda Eva 
Published: January 2023

Abstract
Infection of adult T cell-deficient (TCR βXδ knockout [KO]) mice with the small DNA tumor virus, polyoma (PyV), induces tumor formation, whereas mice that lack αβ T cells but have γδ T cells remain tumor-free after infection. Moreover, infection of E26 transgenic mice, which lack NK cells and all T cells, leads to an accelerated appearance of virus-induced tumors compared to T cell-deficient mice which have NK cells. These observations suggest that both γδ T cells and NK cells are involved in the resistance to PyV-induced tumors. We found that cell lines established from PyV-induced tumors expressed Rae-1, a ligand for the NKG2D activating receptor expressed on both NK and γδ T cells. Therefore, we hypothesized that Rae-1/ NKG2D interactions were involved in the γδT and NK cell-mediated resistance to PyV-induced tumors. Intraperitoneal injection of the tumor cell lines induced an increase in NK cell number in the peritoneal cavity and also resulted in the activation of NK cells and γδT cells there, manifested by IFNγ and granzyme B production; these changes were not seen in mice intraperitoneally infected with PyV. The Rae-1-expressing PyV tumor cells were also killed by NK cells in in-vitro cytotoxicity assays, and anti-NKG2D antibody treatment prevented this killing. These data strongly suggest that interactions of NKG2D activating receptors on NK and γδ T cells with their ligands expressed on PyV-transformed tumor cells are involved in anti-tumor responses in PyV-infected mice.
Supported by NIH grant CA66644
HLA restricted CTL epitope mapping on Hantaan virus nucleocapsid protein in China (128.7)
Authors: Jin Boquan , Wang Meiliang , Zhu Yong , Wang Jiuping , Fang Liang , Ma Ying , Yang Kun , Yang Angang 
Published: January 2023

Abstract
Hantaan virus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS) in humans. Cytotoxic T lymphocyte (CTL) plays an important role in the clearance of the virus. Only few CTL epitopes specific for HTNV have been identified to date. We analyzed by ex vivo ELISPOT the anti-HTNV CTL responses of peripheral blood mononuclear cells (PBMCs) from patients with HFRS. Seventy 15-mer overlapping peptides spanning the entire HTNV nucleocapsid protein were screened with PBMCs of HFRS patients in Shaanxi province, China. A total of 22 15-mer epitopes were identified, in which 19 were defined as CTL epitopes. Furthermore, 13 minimized 9-mer CTL epitopes were defined on 8 of 19 15-mer peptides, in which three were found to be restricted by various HLA alleles including A24, A11 and B7. IFN-γ ELISPOT analysis showed that memory CTL specific for these epitopes were present at high frequency in HTNV-immune individuals many years after acute infection. The identified epitopes may be useful for the design of new HTNV vaccine and the understanding of CTL response to HTNV during acute infection. This work was supported by grants from the National Natural Science Foundation of China (No.30471625).
Protective and Pathologic roles of the Immune Response to Mouse Hepatitis Virus-1 (MHV-1): Implications for Severe Acute Respiratory Syndrome (128.8)
Authors: Khanolkar Aaruni , Hartwig Stacey M , Pewe Lecia L , Varga Steven M , Harty John T 
Published: January 2023

Abstract
Intranasal MHV-1 infection of mice induces lung pathology similar to that observed in SARS patients. However the severity of MHV-1-induced pulmonary disease varies among mouse strains and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS. Little is known about the host immune response to MHV-1 and how it might contribute to some of the pathological changes detected in infected mice. Here we show that an intact Type 1 IFN system, NK cells and the adaptive immune responses are important contributors to the resistance of B6 mice to MHV-1 induced disease. In A/J and C3H/HeJ mice, that are highly susceptible to MHV-1-induced disease, we demonstrate that both CD4 and CD8 T cells contribute to morbidity during primary infection, and memory responses can enhance morbidity and mortality during subsequent re-exposure to MHV-1. However, morbidity in A/J and C3H/HeJ mice can be minimized by treating them with immune serum prior to MHV-1 infection. Overall our findings highlight the role of the host immune response in contributing to the pathogenesis of coronavirus-induced respiratory disease, and have relevant implications for the design of rational vaccine strategies to combat such infections.
Mechanism of host protection against infection with Streptococcus pneumoniae conferred by activation of the aryl hydrocarbon receptor (AhR) (129.11)
Authors: Vorderstrasse Beth A , Akerlund Christine , Wang Tao 
Published: January 2023

Abstract
The AhR is a nuclear receptor whose biological function is under active study. We have found that AhR activation protects mice from infection with S. pneumoniae, a common human pathogen that is a leading cause of death. Specifically, treatment with an AhR agonist lowered pulmonary bacterial burdens in mice and substantially reduced morbidity and mortality. The protective effect was not due to direct toxicity to the bacteria, and did not reflect an enhanced inflammatory response or neutrophil recruitment. The current studies tested the hypothesis that AhR activation within lung epithelial cells inhibited their ability to bind bacteria to reduce invasion. A549 lung epithelial cells were exposed to an AhR agonist (TCDD) and co-cultured with S. pneumoniae. Bacterial adherence was visualized by staining with TTC. The expression of adherence molecules (E-cadherin and PAFR) in lung homogenates was also measured. A second hypothesis was that AhR activation induced the production of a soluble protein that killed bacteria in the lung. Bacteria were cultured in concentrated lung lavage fluid from TCDD-treated infected mice. The results of these experiments did not support the hypothesis that AhR activation within lung epithelial cells altered bacterial adherence or bacterial survival, and future studies will focus on early innate immune cell responses to explain host protection. Supported by NIH/NIEHS and WSU Foundation.
Molecular mechanism of immune evasion by Francisella tularensis through the induction of prostaglandin E2 from infected cells. (129.14)
Authors: Woolard Matthew D. , Fuller James R. , Hensley Lucinda L. , Manoil Colin , Kawula Thomas H. , Frelinger Jeffrey A. 
Published: January 2023

Abstract
Francisella tularensis is a highly virulent gram negative bacterium. Because of the low infectious dose, we investigated possible mechanisms of immune evasion. We have previously demonstrated Francisella tularensis ability to induce the production of prostaglandin E2 (PGE2) from infected cells. PGE2 is a potent regulator of immune responses. Our objective is to identify the F. tularensis product responsible for the induction of PGE2 production. We screened a Francisella transposon mutant library and identified 20 candidate genes. These candidate genes were then expressed in ANA-1s, a macrophage cell line. The expression of open reading frame FTL0119 in ANA-1's caused the macrophage cell line to produce more PGE2 than ANA-1s transfected with other candidate genes. We then generated nonpolar markerless deletions of the FTL0119 ORF in F. tularensis Live Vaccine Strain. As expected, mutant F. tularensis LVS failed to induce the production of PGE2 from bone marrow-derived macrophages. Thus we have identified a gene, FTL0119, which is likely to be directly responsible for the induction of PGE2 from F. tularensis infected macrophages and a contributor to immune evasion.
In MyD88-/- mice infected with Mycobacterium tuberculosis ESAT6-specific CD4 T cells expand normally but display impaired IFN-γ production due to a T cell intrinsic role for the adaptor molecule (129.19)
Authors: Mayer Katrin D , Barber Daniel L , Sher Alan 
Published: January 2023

Abstract
MyD88-/- mice fail to control Mycobacterium tuberculosis (Mtb) replication and rapidly succumb to infection. This phenotype has been attributed to IL-R1 and TLR dependent defects in innate immunity although we have also described impaired Th1 cytokine production in these animals. It is unclear whether the partial defect in Th1 response is due to lack of expansion of antigen (Ag)-specific cells or their failure to differentiate into IFN-γ secreting cells. To address this, we stained with a MHC II tetramer to compare pulmonary I-Ab ESAT61-20 specific CD4 T cells in Mtb infected WT and MyD88-/- mice. Interestingly, expansion of Ag specific CD4 T cells was comparable in the two mouse strains. However, we repeatedly observed an approximate 50% reduction in the frequency of IFN-γ secreting Ag-specific cells in MyD88-/- mice, despite uniform T-bet expression. Non-competitive and competitive mixed BM chimeras were employed to determine whether this IFN-γ production defect reflects a T-cell intrinsic role for MyD88. In both strategies, a significant proportion of Ag-specific MyD88-/- T cells still failed to secrete IFN-γ upon re-stimulation when compared to T cells from WT chimeric controls or MyD88+/+ T cells in the same animal. Thus, in murine Mtb, MyD88 expression is dispensable for expansion but required for optimal IFN-γ secretion by Ag-specific CD4 T cells due largely to a T cell intrinsic function of the adaptor molecule.
Work supported by NIAID Intramural Research Program.
Pathogen-specific regulatory T cells impair protective immunity in tuberculosis (129.25)
Authors: Shafiani Shahin , Heard Glady's T , Jenkins Marc K , Takatsu Kiyoshi , Urdahl Kevin B 
Published: January 2023

Abstract
Following aerosol infection with Mycobacterium tuberculosis (Mtb), Foxp3-expressing regulatory T cells (T regs) proliferate, accumulate at sites of infection, and suppress protective immunity. Here we use TCR transgenic CD4+ T cells specific for an immunodominant Mtb antigen (Ag85B240-254/I-Ab) to investigate the origin and specificity of T regs in tuberculosis. These cells robustly proliferated after transfer into Mtb-infected mice, but did not convert into Foxp3-expressing T regs. Instead, T regs expanded from the pool of Foxp3-expressing cells that existed prior to infection. To further examine the specificity requirements for responding T regs, we used a subset of these transgenic Mtb-specific T cells that co-expressed Foxp3. Only T regs that recognized Mtb antigen proliferated and accumulated at sites of infection and transfer of even small numbers of these cells into infected mice resulted in a higher Mtb burden in the lungs. Using Mtb-specific MHC class II tetramers to track the endogenous pathogen-specific T cell response, Mtb-specific T regs were found to mediate this effect by delaying the appearance of Mtb-specific, IFN-γ-producing CD4+ T cells in the lung, a delay that has been previously associated with impaired resistance to tuberculosis. Our results suggest that individuals containing increased numbers of pathogen-specific T regs will be more susceptible to severe disease.
Novel role for TNF-alpha in memory CD8 T cell-mediated protection against liver stage Plasmodium berghei infection (129.27)
Authors: Butler Noah S. , Schmidt Nathan W. , Harty John T. 
Published: January 2023

Abstract
Malaria results in &gt;1,000,000 deaths per year worldwide. Although no licensed vaccine yet exists, much effort is currently focused on subunit vaccines that elicit CD8 T cell responses directed against liver stage antigens. Multiple T cell effector molecules play a role in anti-microbial immunity mediated by memory CD8 T cells including IFN-gamma, perforin, TRAIL, FasL and TNF-alpha. However, it is not known which effector pathways are required for memory CD8 T cell-mediated immunity to liver stage Plasmodium infection. Here, we used a novel immunization strategy to generate memory CD8 T cells in the wild type and gene-deficient BALB/c mouse model of Plasmodium berghei sporozoite infection to examine the role of these T cell effector molecules in resistance to the liver stage infection. In contrast to previous work examining protection mediated by TCR transgenic effector CD8 T cells, our studies reveal that endogenous memory CD8 T cell-mediated protection is in part IFN-gamma-dependent. Importantly, we also show that neutralization of TNF-alpha in immunized mice markedly reduces memory CD8 T cell-mediated protection. Thus, our studies identify both IFN-gamma and TNF-alpha as important components of the non-cytolytic pathways that underlie memory CD8 T cell-mediated immunity against liver stage Plasmodium infection. Supported by grants from the NIH (to JTH) and an NRSA fellowship (T32AI007260-23 to NSB).
A vaccine containing OprF311-341/OprI/type A- and B-flagellin fusion proteins provides enhanced clearance of nonmucoid Pseudomonas aeruginosa (129.3)
Authors: Weimer Eric , Lu Haiping , Wozniak Daniel , Mizel Steven 
Published: January 2023

Abstract
Although chronic Pseudomonas aeruginosa infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients, there is no approved vaccine for human use against P. aeruginosa. The goal of this study was to establish whether a multivalent vaccine containing type A and B flagellins as well as the outer membrane proteins OprF and OprI would promote enhanced clearance of P. aeruginosa. Intramuscular immunization with flagellins + OprI (separate), or OprI/flagellins fusion proteins generated significant anti-flagellin IgG responses. However, only OprI/flagellins generated anti-OprI IgG. Immunization with OprF311-341/OprI/Flagellins elicited high affinity anti-flagellins, OprI, and OprF-specific IgG. Anti-flagellin, OprI, and OprF IgG promoted deposition of C3 on P. aeruginosa. Although these antibodies exhibited potent antibody-dependent complement-mediated killing of nonmucoid bacteria, they were significantly less effective with mucoid isolates. Mice immunized with OprF311-341/OprI/Flagellins had a significantly lower bacterial burden three days post-challenge and cleared the infection at a significantly faster rate than control mice. Based on our results, OprF311-341/OprI/A- and B-flagellin fusion proteins have substantial potential as a vaccine against nonmucoid P. aeruginosa.
Funded by Cystic Fibrosis Foundation MIZEL0810
Changes in the repertoire of influenza-specific CD8+ T cell responses (130.1)
Authors: Lee Jessica  B , Pipeling Matthew , Oelke Mathias , McDyer John , Ramachandra Lakshmi , Canaday David , Schneck Jonathan 
Published: January 2023

Abstract
Influenza has a high morbidity and mortality rate throughout the world. Geriatric individuals have an increased risk for complications arising from influenza infection and account for over 90% of influenza related deaths. To assess why geriatrics are unable to combat influenza infection as well as adult individuals, we used artificial antigen presenting cells (aAPC) to generate influenza-specific CD8+ T cells ex vivo from healthy donors aged 21-60 and geriatric donors over the age of 65. We found a very diverse response to the subdominant influenza peptides, PB1413-421, NS1123-132, NA231-239, NA75-84, PA46-54, and PA225-233 in the adult donors. While we were able to generate CD8+ T cells against the immunodominant influenza M158-66 peptide in all donors, the geriatric donors lacked the broad, multi-specific response to the subdominant influenza epitopes that we found in the adult donors. These results suggest that aging leads to a hole in the T cell receptor (TCR) repertoire and the presence of CD8+ T cells against subdominant influenza peptides plays a major role in clearance of influenza infection.
Adoptive transfer and pulmonary homing of NK cells rescues NK cell-deficient mice from early lethality during acute influenza A virus infection (130.11)
Authors: Carlin-Brown Lindsey E. , Fullenkamp Colleen A. , McGill Jodi , Legge Kevin L. , Heusel Jonathan W. 
Published: January 2023

Abstract
Natural Killer (NK) cells are vital components of the innate antiviral immune response. NK cells are widely distributed, including the lung (comprising 5-10% of mononuclear cells). We have shown that anti-NK1.1-mediated depletion of NK cells in C57Bl/6 or recombinant-congenic BALB.B6-CT6 mice results in early morbidity and increased mortality to mouse-adapted influenza A virus (IAV), similar to that reported for Ncr1-deficient mice lacking the NKp46 receptor. Adoptive IV transfer of resting CFSE-labeled NK cells prepared from spleen or lung results in pulmonary NK cell reconstitution, with a striking preferential homing of pulmonary NK cells to lung compared to splenic NK cells. NK cell-reconstituted mice are comparable to NK cell-replete controls in morbidity and mortality to acute IAV infection, indicating that adoptive NK cell transfer mediates protection. Future experiments will test the protective capacity of adoptively transferred NK cells deficient in NK cell effector functions (IFN-γ, perforin, TRAIL, or FasL) during acute IAV infection. This novel system will expand our understanding of how NK cells populate the lung and contribute toward early anti-influenza virus immunity.