bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thioredoxin peroxidase secreted by Echinococcus granulosus induces the alternative activation of macrophages in mice (MPF2P.755)
Authors: Wang Hui , Li Jun , Zhang Wenbao , Wen Hao 
Published: January 2023

Abstract
Alternatively activated macrophages (AAM) are key to promoting Th2 responses and have been associated with a variety of roles during helminth infection. We have shown that E. granulosus infection induces a polarized Th2 response in its intermediate hosts. The role of AAM in the regulation of the immune response is unclear. Here we describe the effects of a thioredoxin peroxidase (TPx) derived from E. granulosus, an enzymatic scavenger of H2O2, on murine macrophage phenotype in vivo and in vitro. The activation status of macrophages was analyzed by evaluating the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arg1. AAMs were recruited to the peritoneum of mice of E. granulosus infection. Administration of hydatid cyst fluid (HCF) and recombinant EgTPx or its inactive recombinant variant (rvEgTPx) also induced the recruitment of AAM to the peritoneum indicated that the immunomodulatory property of EgTPx is not due to its antioxidant activity. In vitro studies showed that HCF and EgTPx or rvEgTPx can directly converts PECs from normal mice to an alternatively activated phenotype characterized by the production of high levels of Arg1. Our data suggest that the Th2 responses induced by the E. granulosus infection are mediated through the secretion of molecules, one of which is EgTPx, that induce the recruitment and alternative activation of macrophages.
Memory Tfh cells promote rapid antibody production after secondary Plasmodium yoelii infection (MPF2P.756)
Authors: Wikenheiser Daniel 
Published: January 2023

Abstract
The antibody (Ab)-mediated immune response contributes to protection against a secondary blood-stage Plasmodium yoelii infection. Follicular helper T (Tfh) cells promote B cell survival and facilitate somatic hypermutation and affinity maturation within germinal centers, resulting in the production of high-affinity Ab in a primary infection. The presence of memory T cells is important for the rapid induction of an effector response in secondary infections; however, it is unclear what role memory T cells play in supporting Ab production in a secondary response. Here, we report the identification of a splenic-resident population of CXCR5+ T cells that possess a central memory phenotype (CXCR5+ Tcm) that is maintained greater than 90 days post-P. yoelii infection. Co-transfer of these CXCR5+ Tcm and isotype-switched memory B cells into naive congenic or CD28-/- mice resulted in early plasma cell and germinal center B cell differentiation, as well as class-switched parasite-specific Ab production relative to control mice that did not receive transferred cells. Ultimately, mice receiving CXCR5+ Tcm cells controlled parasitemia more quickly than mice receiving memory B cells alone or no transferred cells. Collectively, these data suggest Plasmodium-specific CXCR5+ Tcm can differentiate into functional Tfh cells upon re-exposure to antigen, and participate in secondary humoral responses leading to rapid production of protective, isotype-switched Abs.
Protective and non-protective CD8 T cell responses against Plasmodium infection (MPF2P.760)
Authors: Doll Katherine , Pewe Lecia , Harty John 
Published: January 2023

Abstract
Despite decades of research, malaria remains a global health crisis. Currently, subunit vaccine approaches do not provide long-term, sterilizing immunity against Plasmodium infection. Conversely, immunization using whole parasites can confer protection in rodents through eliciting protective CD8 T cell responses, likely against a broad spectrum of Plasmodium antigens. However, it is unknown whether all of these CD8 T cell specificities contribute to protection. Recently, four novel H-2b-restricted Plasmodium-specific CD8 T cell epitopes were described from the following antigens: GAP50, PbT, S20, and TRAP. Here, we show that priming with peptide-loaded mature dendritic cells followed by boosting with recombinant L. monocytogenes expressing these epitopes results in memory antigen-specific CD8 T cell responses constituting 5-40% of the CD8 T cell compartment. To date, only TRAP-specific CD8 T cells generated through this vaccination approach can provide sterilizing immunity following a sporozoite challenge. This result occurs despite similar numbers, function and phenotype for each of the memory CD8 T cell populations. These data suggest that timing of antigen presentation during liver-stage infection coupled with a requirement for direct MHC presentation predicts the protective capacity of a CD8 T cell specificity. These data may aid in identifying novel target antigens to elicit sterilizing protection against Plasmodium infection.
Flagellar hook protein FlgE initiates a proinflammatory response via mixed pathways (MPF2P.762)
Authors: Wang Yiqiang , Shen Ying , Yuan Qing , Lin Dandan , Wang Meixiang , Liang Zhongjie , Li Weihua , Tang Hua , Zhang Xuemin , Song Wengang , Zhao Ge 
Published: January 2023

Abstract
Among components of bacterial flagellum, filament flagellin C mediates immunostimulation via TLR5 pathway. Here we showed that hook protein FlgE also participates in host-pathogen interactions and stimulates innate immunity. Recombinant P. aeruginosa FlgE was obtained via routine prokaryotic expression system. After treatment of immortalized human corneal epithelial cells (HCEC) with FlgE, microarray profiling revealed that up-regulated genes were highly enriched in inflammation/immunity-related pathways. Inclusion of anti-TLR5 antibodies or 130mM KCl in culture each partially decreased the effects of FlgE, suggesting a mixed signaling pathways involvement. Pull-down assay performed on FlgE with HCEC lysates and following Mass Spectrum assay of bound proteins suggested that caveolin, membrane type ATP Synthase, Rab5 subunits and prohibitin might couple with FlgE. In an intranasal delivery model in mice as well in an organoid culture of murine lung slices, FlgE induced upregulation of IL1b, IL6 and CXCL1 at both mRNA and protein levels as detected by real-time PCR or ELISA. When administrated with ovalbumin in mice, FlgE enhanced OVA-specific CD4 T cells expansion. 3D modeling of FlgE disclosed two segments that would participate in FlgE polymerization during hook formation, and altering these two sites decreased immunostimulatory potency of FlgE. In conclusion, FlgE bears immunostimulation activity when confronting host cells, and might be used as an immunomodulator/adjuvant.
CD4 signaling and Pneumocystis clearance: a critical role of IL-21R and STAT3 for effector function (MPF2P.745)
Authors: Elsegeiny Waleed , Zheng Mingquan , Eddens Taylor , Alcorn John , Kolls Jay 
Published: January 2023

Abstract
Pneumocystis jirovecii is an opportunist infection that is a significant cause of disease in immunocompromised patients. Patients whose blood CD4 counts drop below 200 cell/μl due to HIV infection or immunosuppressive therapies are at high risk of developing Pneumocystis jirovecii pneumonia (PJP). However, the exact role of CD4 cells and the specific effector subtype that is required for clearance has yet to be determined. We investigated this question with several cytokine and STAT knock out mice using both in vivo infection as well as the assessment of effector CD4+ T-cell function by adoptive transfer into Pneumocystis infected Rag1-/- mice. We observe that classical Th1, Th2, Th17, and Tfh cell effector functions are dispensable for organism clearance. However we found an essential role for both IL21 receptor signaling on CD4 cells as well as CD4+ T-cell intrinsic STAT3 activation are required for clearance. These data are consistent with the recent identification of human IL21R deficiency and susceptibility to PJP. We are currently examining potential novel downstream mechanisms that may mediate immunity against Pneumocystis pneumonia in this context.
Independent of bacterial clearance, interleukin-17A acts to exacerbate pulmonary inflammation in BALB/c mice infected with Mycoplasma pulmonis (MUC1P.901)
Authors: Mize Maximillion , Simecka Jerry 
Published: January 2023

Abstract
As a leading cause of pneumonia in man and animals worldwide, mycoplasmas cause persistent infections that induce debilitating chronic lung inflammation. An incomplete understanding on the pathogenesis of disease has contributed to the absence of effective vaccines against these organisms. Using a naturally occurring murine model mirroring human and animal infections, Interleukin-17A (IL-17A) was found to increase within the lungs of susceptible BALB/c and resistant C57BL/6 mice inoculated with M. pulmonis. In a previous study, C57BL/6 mice deficient in IL-17 receptor expression were shown to have impaired clearance of mycoplasma. We hypothesized that IL-17A may have a different role in susceptible BALB/c mice. Consistent with this idea, we report that injection of neutralizing antibodies against IL-17A reduced respiratory inflammation in BALB/c infected with M. pulmonis. This was seen through abrogated lymphoid and neutrophil recruitment when compared to littermate controls. In addition, both gross lung and alveolar lesions were significantly reduced upon IL-17A neutralization. Surprisingly, blocking IL-17A did not alter bacterial burden, thus solely influencing the inflammatory process during infection in BALB/c mice. Interestingly, anti-IL-17A antibody administration did not have an effect on mycoplasma infection in resistant C57BL/6 mice, suggesting that the IL-17A pathways differ between susceptible and resistant strains of mice.
A novel subset of lung tissue-resident memory CD4 T cells generated by influenza virus infection (MUC1P.903)
Authors: McKinstry Karl , Strutt Tara , Swain Susan 
Published: January 2023

Abstract
We recently identified a late IL-2-dependent ‘checkpoint’ during the effector phase of the T cell response against influenza A virus (IAV) that is required for the generation of most long-lived CD4 T cell memory. Here, we describe a novel subset of IL-2- and IL-7-independent IAV-specific memory CD4 T cells that survive only in the lung (the site of IAV infection). These cells (i) are shielded from labeling by fluorescent anti-CD4 antibodies administered intravenously, (ii) express a CD69high, CD127low surface phenotype, and (iii) are highly functional upon re-stimulation both in terms of cytokine production and the ability to rapidly activate dendritic cells. These characteristics are consistent with recently described ‘tissue-resident’ memory T cells (Trm). In contrast to most described CD8+ Trm populations, the IAV-specific CD4+ Trm are not CD103high, and do not require TGF-β signaling for their generation. We show that this novel CD4+ Trm subset survives poorly upon adoptive transfer to unmanipulated hosts, suggesting that this Trm subset is adapted to survive in a unique non-lymphoid niche. Transcriptional analysis further supports this hypothesis as broad differences distinguish Trm from conventional memory CD4 T cells present in the lung. In summary, our studies identify a population of IAV-specific Trm CD4 T cells that develops independently of signals required for the generation of virtually all other subsets of CD4+ memory T cells.
Nasal plasmid Flt3 ligand and CpG ODN alone enhances immediate, influenza virus-specific recall secretory IgA Ab responses in aging (MUC1P.904)
Authors: Ohori Junichiro , Asanuma Hideki , Aso Kazuyoshi , Ikeda Yorihiko , Sugita Gen , Fujihashi Keiko , McGhee Jerry , Fujihashi Kohtaro 
Published: January 2023

Abstract
The elderly have already experienced various pathogens and thus possess pathogen-specific Abs, whose titers are too low to combat reinfection. Thus, it would be of great benefit to the aged population if one could use an innate adjuvant system alone, without vaccine, in order to enhance mucosal immunity against past respiratory infections. We tested whether a combined plasmid Flt3 ligand (pFL) and CpG ODN adjuvant would enhance influenza virus-specific recall Ab responses without a need for additional vaccination. Young adult mice were nasally immunized with A/Puerto Rico/8/34 (PR8) hemagglutinin (HA) plus cholera toxin as mucosal adjuvant three times at weekly intervals. Seven months later, these mice were given nasal pFL and CpG ODN only or combined adjuvant together with PR8 HA. Saliva and plasma samples were collected 7 days later and PR8 HA-specific IgA Ab responses were evaluated. Both groups of mice showed significantly increased and comparable levels of anti-PR8 HA secretory IgA Ab responses in saliva when compared with those responses seen without innate adjuvant. The increase in total IgG Ab responses in mice given pFL and CpG ODN were limited when compared with those seen after primary nasal immunization. Total plasma IgE Ab titers in mice given nasal pFL and CpG ODN only were the same as IgE levels seen in naïve mice. These results suggest that nasal pFL and CpG ODN alone can enhance pre-existing Ag-specific Ab responses without adverse effects in the elderly.
MAVS plays an essential role in host immunity against human metapneumovirus (MUC1P.907)
Authors: Chen Yu , Liu Guangliang , Ren Junping , Ivanciuc Teodora , Casola Antonella , Garofalo Roberto , Bao Xiaoyong 
Published: January 2023

Abstract
Human metapneumovirus (hMPV) is a common cause of respiratory tract infection in the pediatrics population. Recently, we and others have shown RIG-I-like receptors are essential for hMPV-induced cellular antiviral signaling. However, the contribution of those receptors in host immunity against pulmonary hMPV infection is largely unexplored. In this study, mice deficient in MAVS, an adaptor of RIG-I-like receptors, was used to investigate the role(s) of these receptors in pulmonary responses to hMPV infection. MAVS deletion significantly impaired the induction of IFN-I and other proinflammatory cytokines by hMPV. Compared to wild type mice, mice lacking MAVS harbored a higher viral load and demonstrated impaired abilities to activate pulmonary dendritic cells (DCs), subsequently leading to abnormal memory T cell responses to hMPV infection. In addition, we found that MAVS is required for the recruitment of DCs and other immune cells to the bronchoalveolar lavage fluid (BALF). Taken together, our data indicate that MAVS-mediated pathways are essential for the pulmonary immune responses, both innate and adaptive, to hMPV infection.
Border patrol gone awry: lung NKT cell activation by F. tularensis exacerbates tularemia-like disease (MUC1P.908)
Authors: Hill Timothy , Gilchuk Pavlo , Cicek Basak , Boyd Kelli , Khanna Kamal , Joyce Sebastian 
Published: January 2023

Abstract
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning for border patrol, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia—because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain results in rapid recruitment of NKT cells to the lung interstitium. Interstitial NKT cell activation resulted in protective interferon-γ production, and affected both local and systemic proinflammatory responses. Hence, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet survived the infection whilst their wild type counterparts did not. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F tularensis infection hampers iBALT formation, which in conjunction with NKT cell-dependent proinflammatory response causes severe pulmonary tularemia-like disease in mice.
Selective programming of regulatory CCR10+ innate lymphoid cells in skin-draining lymph nodes for skin immune homeostatic regulation (MUC2P.918)
Authors: Yang Jie , Hu Shaomin , Xiong Na 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) are preferentially localized in barrier tissues where they function in homeostatic regulation but also contribute to inflammatory diseases. Mechanisms regulating establishment of ILCs in barrier tissues with diverse functions in homeostasis and inflammation are poorly understood. We found that microenvironments of lymph nodes (LNs) program ILCs with homing and functional potentials for their tissue-specific functions. In skin- but not mucosal tissue-draining LNs, ILCs were continuously activated to acquire regulatory properties with high expression of CCR10 for their localization into the skin. Upon analyzing Rag1-/-, Foxn1-/-, Foxp3-/- and skin-inflammation-induced mice, we found that the generation of CCR10+ ILCs in skin-draining LNs and their establishment in the skin required T cell-regulated homeostatic environments and were suppressed during inflammation. Reciprocally, CCR10+ ILCs also promote homeostasis of resident T cells. When transferred into IL2Rγ-/-Rag2-/- mice that lack ILCs, CD4+ T cells could not establish homeostasis in the skin, with notably reduced regulatory T cells and increased effector T cells expressing high levels of inflammatory cytokines, demonstrating cross-regulation of CCR10+ ILCs and CD4+ T cells to promote immune homeostasis in the skin. Our studies reveal a process programming tissue-specific ILCs in LNs for their localization and function in local tissues.
Obesity impairs lymphocyte homeostasis and function in epithelial tissues via inflammatory mechanisms (MUC2P.932)
Authors: Jameson Julie , Cheung Kitty , Costanzo Anne , Limon Natalie , Yee Christine , Park Christa 
Published: January 2023

Abstract
Barrier tissues such as the skin and intestine provide vital protection to the organism from pathogens and exposure to the environment. Epithelia-resident γδ T lymphocytes maintain this protective barrier via the production of growth factors and cytokines. Obesity and type 2 diabetes disrupt normal homeostasis within the epithelium and result in complications that include delayed tissue repair. We have previously identified a reduction in the number of T cells within the epithelium of the skin and intestine of mice as obesity progresses. Here we find that obesity impairs the ability of lymphocytes to maintain homeostatic proliferation within epithelial tissues. Our studies show that this is particularly devastating in young mice that are still establishing lymphocyte populations in their epithelia. Using blocking studies and gene chip analyses we have identified inflammatory mediators that are involved in the negative impact that obesity has on intraepithelial lymphocytes. The mechanism involved is independent of diet as both mice on a high fat diet and genetically obese mice on a normal chow diet exhibit reduced and dysfunctional epithelial lymphocytes. Reducing chronic inflammation by weight loss or blocking inflammatory mediators begins to reestablish T cell homeostasis and improve tissue repair. This data identifies new therapeutic targets for improving tissue repair during obesity and type 2 diabetes via the restoration of normal cellular homeostasis and gene expression.
Resolvin E1 regulates contact hypersensitivity responses by inhibiting dendritic cell functions through leukotriene B4-BLT1 signaling blockade (MUC2P.936)
Authors: Sawada Yu , Honda Tetsuya , Nakamura Motonobu , Miyachi Yoshiki , Kabashima Kenji 
Published: January 2023

Abstract
Resolvin E1 (RvE1) is a lipid mediator derived from ω3 polyunsaturated fatty acids that exert potent anti-inflammatory roles in several disease models. However, the precise underlying mechanism how RvE1 exerts its action in vivo remains largely unknown. In this study, we investigated the mechanisms of the anti-inflammatory effect of RvE1 using a contact hypersensitivity model. We found that administration of RvE1 significantly suppressed skin inflammation through a blockade of BLT1, a leukotriene B4 (LTB4) receptor, on dendritic cells (DCs). Live imaging of cutaneous DCs by two-photon microscopy revealed that RvE1 significantly impaired DC motility in the skin and migration to draining lymph nodes as well as antigen presentation ability in the skin. LTB4-BLT1 signaling induced actin formation in DCs and increased DC motility by activating Cdc42 and Rac1 through the PI3 kinase pathway, which was canceled by the administration of RvE1. Taken together, our results indicate that RvE1 attenuates cutaneous immune responses by inhibiting cutaneous DC functions through LTB4-BLT1 signaling blockade.
Robust Th17 response to intranasal group A streptococcal infection requires IL-6 produced by CD301b+CD11b+CD103- migratory dendritic cells (MUC2P.937)
Authors: Dileepan Thamotharampillai , Linehan Jonathan , Cleary P. , Jenkins Marc 
Published: January 2023

Abstract
Intranasal (i.n.) Group A Streptococcal (Streptococcus pyogenes - Sp) infections generate a vigorous Th17 response. We tested the hypothesis that a specific dendritic cell (DC) subset in the nasal associated lymphoid tissue and cervical lymph nodes (CLN), preferential sites of colonization and lymphatic drainage site for i.n. Sp, are responsible for this skewing of the T cell response. The hypothesis was tested by tracking polyclonal Sp peptide:MHCII-specific CD4+ T cells mice lacking specific DC subsets. We found that Sp peptide:MHCII-specific Th17 formation depended on an IL-6 producing CD301b+ CD11b+ CD103- migratory DC population in the CLN. The results contrast with other findings implicating CD11b+ CD103+ DC in Th17 induction in the intestinal mucosa. Therefore, different DC subsets are responsible for Th17 generation through different mucosal surfaces.
Recirculating HIV-target T lymphocytes at the mucosal surface of the female genital tract are associated with progesterone increases during the menstrual cycle (MUC2P.938)
Authors: Swaims Alison , Haaland Richard , Evans-Strickfaden Tammy , Haadad Lisa , Sheth Anadi , Lupo L. , Cordes Sarah , Aguirre Alfredo , Lupoli Kathryn , Chen Cheng-Yen , Ofotokun Igho , Kohlmeier Jacob , Hart Clyde 
Published: January 2023

Abstract
The Female Genital Tract (FGT) provides a means of entry to opportunistic infections, including HIV, yet immune cell populations at this mucosal surface are poorly defined. We initiated a study of 20 healthy women to characterize resident T cell populations in the lower FGT from lavage and patient-matched blood samples. Surprisingly, we report FGT T cells were primarily CCR7hi memory CD4 T cells (P=&lt;0.0001), consistent with a central memory phenotype and known HIV reservoir. FGT CCR7hi T cells exhibited more frequent expression of HIV susceptibility markers CCR5 and CD38 compared to blood (0.6% vs. 13.6%, P=0.0017), yet retained the ability to migrate to CCR7 ligands, suggesting these cells could migrate from the genital tract into afferent lymphatics. Finally, we demonstrate the frequency of FGT CCR7hi target cells increased during the luteal phase of the menstrual cycle (51.7-72.7), and correlated to progesterone from patient-matched blood (r=0.5176, P=0.0024). These data show that a majority of CD4 T cells at the surface of the FGT in humans do not express canonical resident memory T cell markers, but are primarily a central memory T cell phenotype with the ability to traffic across the mucosal epithelium into underlying tissue. Our findings suggest HIV may directly infect recirculating memory CD4 T cells that traffic virus across the FGT mucosal barrier and progesterone changes throughout the menstrual cycle may predict availability of these cells HIV target cells.