bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sialophorin is necessary for vaccine-induced CD8+ T cell responses and immunity against lethal fungal pneumonia in CD4+ T-cell deficient hosts
Authors: Mudalagiriyappa Srinivasu , Nanjappa Som G. 
Published: February 2023

Abstract
Increased opportunistic fungal infections in immunocompromised patients and lack of effective therapeutic modalities caused millions of deaths worldwide. Further, there are no licensed vaccines available for such and for immune-sufficient individuals. Previously, we have shown that in the absence of CD4+ T cells, vaccine-induced CD8+ T cells can mount sterilizing fungal immunity. However, molecules that have an immunomodulatory effect on CD8+ T cells are still to be explored. Using a mouse model of CD4+ T cell lymphopenia and experimental fungal vaccine, we demonstrate that Sialophorin (CD43), a molecule deficient in WAS patients, plays a critical role in mounting anti-fungal immunity. Genetic ablation of CD43 resulted in blunted CD8+ T cell responses associated with reduced expression of prototypic lineage-specific transcription factors following vaccination. Cell-intrinsic expression of CD43 on CD8+ T cells was indispensable for their expansion. Poor vaccine-induced effector CD8+ T cell responses under CD43-deficiency caused the failure to control fungal pneumonia following lethal challenge, independent of trafficking defect of the CD43-deficient effector cells. Further, we demonstrate antigen-specific CD8+ T cells preferentially expressed glycosylated-CD43. Notably, the numbers of glycosylated-CD43+ CD8+ T cells were directly correlated with vaccine-immunity. Thus, the glycosylated-CD43 expression on the CD8+ T cells could serve as a biological marker of vaccine efficacy and clinical outcome of fungal pneumonia. In conclusion, we report that CD43 is required for effective vaccine-immunity against lethal fungal pneumonia, and glycosylated-CD43 could be a novel phenotypic T-cell marker of fungal immunity.
Prime-Trap immunization with protective liver stage antigen, MIF-4G and Kb17 peptide, induces liver CD8 TRM cells and protection against Plasmodium berghei malaria
Authors: Krzych Urszula , Althubaiti Nouf , Pichugin Alexander V , Duffy Patrick E , Zarling Stasya N 
Published: February 2023

Abstract
Exposure to Plasmodium sporozoites (spz), the causative agent of malaria, induces anti-disease immunity, but fails to protect against repeated Plasmodium infections. In contrast, multiple immunizations with radiation-attenuated Plasmodium spz (RAS) induce sterile lasting protection in humans, non-human primates, and murine models. The mechanisms of protective immunity are multifactorial and CD8 T cells are considered sine qua none of protection. The Plasmodium berghei (Pb) RAS-induced protection in C57Bl/6 mice correlates with a network of liver stage antigens (LS Ags)-activated liver CD8 T cell subsets including resident memory (RM) CD8 TRM cells. A protective Pb LS Ag, termed MIF-4G, induced liver CD8 T cells that recognize H-2Kb-restricted epitope, Kb17. One of the current efforts to improve malaria vaccines focuses on maximizing the induction of liver CD8 TRM cells by Prime-Trap immunization regimen. Here we asked if priming with DNA-MIF-4G followed by trapping with Adenovirus serotype 5 (Ad5) vectored-Kb17 would induce Kb17-specific liver CD8 TRM cells as well as protection against Pb spz challenge. Liver Kb17-specific CD8 TRM cells (CD69+CXCR6+) exceeded the number of these cells in the spleens, 27% vs 2%, respectively. Protection measured by liver parasite burden was CD8 T cell dependent. In contrast, prime:boost immunization with DNA/Ad5 MIF-4G induced only 8% liver CD8 TRM cells, as did control immunization with DNA/Ad5 empty vector. Utilizing LS Ags and the corresponding CD8 T cell-inducing epitopes in Prime-Trap immunization lends itself for further explorations as an ancillary approach to malaria vaccine regimens where liver CD8 TRM may be crucial in preventing virulent blood stages by targeting LS parasites.
Early Life Imprinting of a Th2-Stromal Cell Niche in Skin
Authors: Boothby Ian C , Boda Devi P , Kwan Elaine Y , Cohen Jarish N , Habrylo Ireneusz , Molofsky Ari B , Rosenblum Michael D 
Published: February 2023

Abstract
Tissue inflammation early in life can be imprinted on the immune system, causing lasting changes in immunologic tone that confer disease protection or susceptibility in adults. The cellular and molecular mechanisms responsible for immune imprinting in many nonlymphoid tissues remain largely unknown. We find that time-limited neonatal inflammation induced by transient reduction of regulatory T cells (Tregs) causes a dramatic dysregulation of skin stromal cells, accompanied by the selective accumulation of Th2 cells within a distinct microanatomic tissue niche. Th2 cells are maintained into adulthood through interactions with a previously uncharacterized stromal population in skin fascia that we refer to as Th2-interacting fascial fibroblasts (TIFFs), which expand following Treg reduction, respond to Th2 cytokines, and produce IL-33. Formation of the Th2-TIFF niche imprints skin with increased reparative capacity after wounding. Taken together, these data define a novel Th2 niche in skin and suggest a mechanism of immunologic imprinting whereby inflammation early in life creates networks between adaptive immune cells and parenchymal cells, establishing an immunological set-point in tissues that is maintained throughout life.
γδ T cells control gut pathology in a chronic inflammatory model of colorectal cancer
Authors: Dasgupta Suryasarathi , Liu Hong , Bailey Brandi , Wyrick Corey , DeBoever Chris , Grieves Jessica , Faustin Benjamin , Murphy Craig 
Published: February 2023

Abstract
Gut gd T cells are important intraepithelial lymphocytes with critical roles in maintenance of gut barrier integrity against infection and cancer, through unknown mechanisms. In addition to their role in barrier function, absence of gd T cells has been reported to lead to faster polyp formation in an inflammation unassociated model of colorectal cancer (CRC). The significant linkage between Inflammatory Bowel Disease and CRC is of strong relevance in gut translational research, and it necessitates a deeper understanding of the underlying cell-molecular mechanism causing inflammation associated CRC. In a new disease-relevant, chronic inflammation associated Colorectal cancer (CRC) model, we observed enhanced chronic colon pathology for both inflammation and polyp formation in mice lacking gd T cells. RNAseq analysis of colon from TCR d−/− mice treated with AOM-DSS revealed an early and profound dysregulated transcriptional landscape with reduced tumor suppressive genes, upregulated tumor induction and epithelial mesenchymal transition genes, and increased expression of inflammatory markers. As tumorigenesis progressed, colons lacking gd T cells harbored enhanced potentially immunosuppressive CD4 T cells in the epithelial layer but not in the lamina propria. Consistently, the gut gd T cell dependent tissue signature identified is positively correlated with different stages of colon adenocarcinoma in patients. Taken together, we demonstrate that gd T cells display broad tissue functions critical in gut homeostasis by controlling both epithelial and immune functions, and maintain tissue integrity against CRC.
Regulatory mechanism of fucoidan-mix AG in intestinal mucosal immune cells
Authors: Miyazaki Yoshiyuki , Bak Juneha , Nakano Hayato , Takeuchi Shugo , Takeuchi Hideaki , Tachikawa Daisuke 
Published: February 2023

Abstract
Fucoidan is a series of natural sulfated polysaccharides contained in brown sea algae, and their beneficial physiological activities such as anti-tumor, anti-virus and immune regulatory effects have been reported. In previous studies, we proved that fucoidans derived from Cladosiphon okamuranus (C. okamuranus) and Undaria pinnatifida effectively improved anti-tumor immunity and tumor vaccine efficiency in combination with an Agaricus blazei mycelium extract. It is thought that the fucoidan-agaricus mix (named fucoidan-mix AG) stimulate innate immune cells to activate intestinal and mucosal immune reaction, but actual target immune tissues and cells by fucoidan have not been evidenced yet. In this study, we investigated action mechanisms of fucoidan in regulation of mucosal immune activities. At first, immune cells were isolated from Payer’s patches, mesenteric lymph node (MLN) and intestinal epithelia of Balb/c mice, then stained with fluorophore-labeled fucoidan. As the results, it was revealed that fucoidan directly interact with lymphocytes besides dendritic cells and macrophages existing in these intestinal immune tissues. Furthermore, immune cells from Payer’s patches and MLN stimulated with fucoidan from C. okamuranus and fucoidan-mix AG produced more TNF-α, IL-12 and Th1 cytokine IFN-γ. The production of an immunosuppressive cytokine IL-10 also was augmented in the fucoidan-treated immune cells, which suggesting that fucoidan balanced immune system to prevent occurrence of excessive reaction. In addition, it was newly proved that fucoidan directly stimulated T lymphocytes to induce enhanced IFN-γ production.
Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal immunity
Authors: Onder Lucas , Prados Alejandro , Koliaraki Vasiliki , Mörbe Urs Michael , Lütge Mechthild , Cheng Hung Wei , Ludewig Burkhard , Kollias George 
Published: February 2023

Abstract
Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying of FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer’s patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate-mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate-mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anti-coronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.
Antigen-specific T cell tolerance in the prevention of post-infectious myocarditis induced with Coxsackievirus B3
Authors: Reddy Jay , Arumugam Rajkumar , Lasrado Ninaad , Renu Sankar , Gourapura Renukaradhya J 
Published: February 2023

Abstract
Of the many types of heart disease, myocarditis is a predominant cause of heart failure in adolescents, and 10–20% of those affected can develop dilated cardiomyopathy (DCM) with infiltrates in their hearts. Autoimmunity resulting from exposure to infectious agents such as Coxsackievirus B3 (CVB) has been suggested as a possible underlying mechanism of chronic myocarditis in the development of DCM. We recently demonstrated that CVB infection could lead to the generation of pathogenic autoreactive T cells leading to a suggestion that their effector functions can be suppressed by developing antigen-specific T cell therapies. To this end, we sought to generate induced Treg cells by using biodegradable nanoparticle delivery system made of chitosan and poly(lactic-co-glycolic acid) (PLGA) entrapped with interleukin-2 and transforming growth factor termed, nanocytokines. Our data suggest that the PLGA nanocytokines can stably induce Forkhead box protein P3, a molecular marker of Treg cells accompanied with complete suppression of interferon-γ production. Our preliminary data indicate that the Treg cells induced with nanocytokines can suppress non-Treg cells in vitro leading to a suggestion that they could be used to prevent the expansion of autoreactive T cells generated in mice affected with viral myocarditis.
Tissue-specific complement inhibition by antibody-Complement Regulatory Protein (CRP) fusions utilizing Therapeutic Autoimmune reguLatOry proteiN (TALON™) platform
Authors: Jung Jiwon , Larkin Bridget M , Rajani Gaurav , Borah Minasri , Nagy-Domonkos Celesztina , Zhou Weijie , Otipoby Kevin L , Viney Joanne L , Higginson-Scott Nathan , Mascanfroni Ivan , Shaheen Hussam H 
Published: February 2023

Abstract
The complement system plays a major role in humoral innate immunity. Upon activation, complement proteins trigger a cascade of enzymatic events leading to the production of inflammatory mediators and membrane attack complexes. Tight regulation of complement proteins is essential for immune homeostasis due to their potency and abundance in fluid phase. Complement Regulatory Proteins (CRPs) that are membrane-bound (e.g., CD59), or in fluid phase (e.g., Factor H), prevent aberrant activation of complement pathways against self and mitigate autoimmunity. The importance of CRPs is underscored by the finding that genetic variations in the CRPs can lead to autoimmune diseases such as paroxysmal nocturnal hemoglobinuria (PNH) characterized by the lysis of host red blood cells from dysregulated complement system.
Systemic complement inhibition via anti-C5 antibody has clinically been shown to benefit some patients with complement-mediated disorders, but the therapy requires a high, frequent dosing scheme and supplemental vaccinations to compensate for systemic immunosuppression. In addition, other diseases such as C3 glomerulopathy affect specific tissues and involve pathways beyond C5, limiting treatment options. To this end, local immunomodulation through targeted delivery of CRPs to specific tissues is an attractive strategy to restore homeostasis in complement-mediated autoimmune diseases while circumventing the need for high dose systemic inhibition of complement factors. Here, we present a proof-of-concept study for the design, generation, and evaluation of tissue-tethering antibodies fused with CRPs. Also, we demonstrate the pharmacokinetics and pharmacodynamics of tissue-targeting CRP fusions in mouse models.
4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis
Authors: Kuo Ping-Chang , Weng Wen-Tsan , Brown Dennis A. , Scofield Barbara A. , Paraiso Hallel C. , Yu I-Chen , Yen Jui-Hung 
Published: February 2023

Abstract
Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, and neuronal damage. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. Presently, growing evidences show that phenolic compounds exert anti-inflammatory effects by inhibiting the production of inflammatory molecules. 4-ethylguaiacol (4-EG), a phenolic compound, which was detected in foods, such as green bell peppers, corns, sesames, and coffee has been shown to possess anti-inflammatory effects through attenuating peripheral immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unexplored. In this study we assessed the therapeutic effect of 4-EG in EAE using both chronical and relapsing-remitting animal models. Our results showed that 4-EG not only ameliorated disease severity in chronic EAE but also mitigated disease progression in relapsing-remitting EAE. Further investigations revealed that 4-EG suppressed MG activation, inhibited Th1 and Th17 infiltration, and mitigated BBB disruption in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE. Finally, 4-EG induced HO-1 expression in the CNS of EAE as well as in MG and macrophages. In summary, our work demonstrates for the first time that 4-EG confers a protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1/Th17 differentiation, suggesting that 4-EG could be developed as a therapeutic agent for the treatment of MS/EAE.
Generation of islet antigen-specific engineered Tregs for use in T1D therapy via homology-directed gene editing of conventional CD4+ T cells
Authors: Yang Soo Jung , Singh Akhilesh K , Tappen Tori , Honaker Yuchi , Mauk Kelsey , Smith Jessica , Sommer Karen , Rawlings David , Buckner Jane H 
Published: February 2023

Abstract
Adoptive transfer of regulatory T cells (Tregs) is therapeutic in T1D mouse models. Notably, Tregs specific for pancreatic islets were shown more potent than polyclonal Tregs in blocking disease. However, the frequency of antigen-specific Tregs is extremely low and ex vivo expansion has the potential risk to destabilize Tregs leading to an effector phenotype. Here, we developed methods to generate durable, antigen-specific engineered Tregs (EngTregs) from primary human CD4+ T cells using a combination of lentiviral TCR transduction and FOXP3 homology-directed repair (HDR)-editing. Using TCRs derived from clonally expanded islet-reactive CD4+ T cells in T1D, we generated islet-specific EngTregs that exhibit a Treg-like phenotype. Islet-specific EngTregs effectively suppress proliferation and cytokine production by islet-specific effector T cells (Teff). Notably, EngTregs suppress Teff recognizing the identical peptide as well as bystander Teff recognizing alternative islet antigens. Importantly, islet-specific EngTregs suppress polyclonal endogenous islet-specific T cells derived from PBMC of individuals with T1D. To directly assess the capacity of EngTregs to modulate diabetes in vivo, we established an identical HDR-editing strategy in islet-specific murine cells. Following adoptive transfer, islet-specific mu-EngTregs homed to the pancreas and blocked diabetes triggered by islet-specific Teff in recipient mice. Collectively, our approach enables the production of EngTregs specific to pancreatic islets with the capacity to efficiently suppress islet specific responses. This approach has the capacity to deliver targeted islet specific therapy to treat or prevent T1D.
Mannose Conjugated Chitosan-based Influenza Nanovaccine Intranasal Inoculation Enhances the Cross-reactive Immunity in Maternal Antibodies Positive Pigs
Authors: Gourapura Renukaradhya J , Feliciano-Ruiz Ninoshkaly , Patil Veerupaxagouda , Schrock Jennifer , Han Yi , Ramesh Anikethana , Dhakal Santosh , Krakowka Steven , Renu Sankar 
Published: February 2023

Abstract
Swine influenza A virus (SwIAV) causes respiratory tract infection in pigs. Parenteral administration of inactivated SwIAV vaccine in weaned piglets provides variable protection due to preexisting specific maternal derived antibodies (MDA). We developed killed SwIAV antigen (KAg) encapsulated mannose-conjugated chitosan nanoparticles (mCS NPs-KAg) vaccine which targets dendritic cells. In MDA-positive piglets, prime-boost intranasal inoculation of mCS NPs-KAg vaccine elicited enhanced homologous (H1N2-OH10), heterologous (H1N1-OH7), and heterosubtypic (H3N2-OH4) influenza virus-specific secretory IgA (sIgA) antibody response in nasal passage compared to control CS NPs-KAg vaccinates. In both mCS NPs-KAg and CS NPs-KAg vaccinates upon challenge with a heterologous virus observed augmented cross-reactive virus-specific sIgA antibody response in nasal swab, lung lysate, and bronchoalveolar lavage (BAL) fluid, and IgG antibody levels in lung lysate and BAL fluid samples. Whereas the multivalent commercial inactivated SwIAV vaccine administered intramuscular had increased only the specific serum IgG antibody response. Additionally, mCS NPs-KAg vaccine increased the specific recall lymphocyte proliferation, and the frequency of IFNγ secreting T cells, late effector and effector memory T cells, and cytokines IL-4, IL-10, and IFNγ gene expression compared to CS NPs-KAg and commercial SwIAV vaccinates. Both the mCS NPs-KAg and CS NPs-KAg vaccines efficiently cleared the challenge virus load from airways and reduced the lung lesions compared to commercial vaccine. Overall, mCS NP-KAg vaccine in MDA-positive pigs induced a robust cross-reactive immunity and offered cross-protection against influenza virus.
Immunogenetic variation at MHC class I loci in desert bighorn sheep (Ovis canadensis nelsoni) reflects natural and anthropogenic fragmentation
Authors: Dolan Brian P , Beechler Brianna , Dugovich Brian , Jolles Anna , Epps Clinton 
Published: February 2023

Abstract
Desert bighorn sheep (Ovis canadensis nelsoni) are a charismatic ungulate native to western North America that live in mountainous regions. In the desert of the southwest United States, populations of bighorn sheep can be isolated by both natural and anthropogenic barriers. Isolation limits gene flow, exacerbates loss of genetic diversity to drift, and thus could affect immune responses to infectious agents. We sought to develop a relatively rapid method for determining MHC class I gene diversity in individual sheep. Both DNA and RNA were isolated from leukocytes collected from 154 adult bighorn sheep from across different mountain ranges in Southern California. Previously identified primers from domestic sheep were used to amplify exons 2 and 3 from OMHC I genes while appending adapters for PacBio circular consensus sequencing. We successfully identified over 40 unique MHC class I sequences expressed by bighorn sheep. Using a combination of phylogenic tree analysis and mapping MHC sequences to the domestic sheep genome, we detect at least 4 unique classical MHC class I regions. Comparison of results using either genomic DNA or mRNA (cDNA) as a template for analysis suggest that certain MHC alleles are expressed at different levels within leukocytes, while many potential pseudogenes were identified when genomic DNA was used as a template. Our data suggests using messenger RNA (cDNA) as a template to identify MHC class I diversity is superior to genomic DNA. Finally, we found clear patterns of MHC class I genotypes differentiated by population, which suggests that both natural and anthropogenic-induced population fragmentation can limit the diversity of MHC genes within a given population.
Innate and Adaptive Responses to Bacillus Calmette-Guerin in Young Pigs
Authors: Byrne Kristen A , Loving Crystal L 
Published: February 2023

Abstract
Development of novel antibiotic alternatives is a critical One Health priority impacting both human and animal wellbeing. While the attenuated strain of M. bovis (Bacillus Calmette-Guerin, BCG) was developed as a vaccine against tuberculosis; recently, BCG has been observed to alter circulating monocytes leading to enhanced inflammatory immune responses to heterologous agonists. These changes can persist for months after the initial BCG exposure, and may serve to enhance innate immune health and reduce disease without the use of antibiotics. Following in vitro observation of innate training in pig monocytes, we wanted to study in vivo BCG responses in pigs as a potential path to enhance innate immunity. Young pigs were inoculated with BCG and weeks later ex vivo cytokine responses to innate TLR agonists and IFNγ response to M. bovis purified protein derivates (PPDb) were measured. PPDb stimulated PBMCs from pigs inoculated subcutaneous with 107 CFU of BCG produced the highest amount of IFNγ as compared to intramuscular inoculated or 106 CFU inoculated pigs. No differences were observed in PBMCs or monocytes stimulated ex vivo with TLR agonists between control and BCG inoculated pigs regardless of route or dose administered. Unlike cattle and humans, in pigs BCG does not seem to readily disseminate from the inoculation site, which may explain the lack of altered innate immune responses observed. Differences in adaptive immune responses indicated alterations to dose or route of BCG administration impacted immunogenicity. Future studies will employ intravenous BCG administration to understand if peripheral exposure to BCG is required to alter innate responses in circulating pig monocytes.