bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of Interleukin-10 signaling during BCG vaccination enhances protection against Mycobacterium tuberculosis infection in mice
Authors: Dwivedi Varun , Headley Colwyn , Ault Russell , Torrelles Jordi , Turner Joanne 
Published: January 2023

Abstract
Interleukin-10 (IL-10) is a major immune regulator in Mycobacterium tuberculosis (M.tb) infection. We have shown that the absence of IL-10 signaling during early phases of M.tb infection results in enhanced protection in mice. We further showed that BCG immunization alone induces IL-10 production in the lungs as early as day 7. We therefore hypothesized that blocking IL-10 signaling during BCG vaccination would increase the magnitude of protection against M.tb challenge. Mice were subcutaneously co-immunized with a single dose of anti-IL-10R1 or respective IgG1 isotype antibody with BCG followed by low dose aerosol M.tb infection 6 weeks later. Protective efficacy was determined at day 30 and 120 post challenge. BCG/anti-IL-10R1 immunized mice showed a significant reduction (~1.5 log) in M.tb CFU in the lungs at day 120, compared to control mice. CD4+ and CD8+ T cell populations in BCG/anti-IL10R1 immunized mice (in the absence of M.tb infection) showed significant increases in central memory markers in the lung at day 7, which reduced at day 28 post immunization. Effector memory markers were reduced in CD4+ T cells at day 7 and increased at day 28 in BCG/anti-IL-10R1 immunized mice but were unchanged in CD8+ T cells. Our findings demonstrate that transient IL-10 signaling blockade during BCG vaccination alters memory T cell populations and results in long-term protection against M.tb challenge. Our findings are relevant to vaccine development in humans as they demonstrate that modulation of IL-10 at the time of vaccination can generate long-term protective efficacy against M.tb.
Infection-permissive immunity against influenza virus provided by vaccination prevents loss of alveolar macrophages and modulates virus-induced cross-reactive cellular immune responses during subsequent influenza infections.
Authors: Schotsaert Michael , Choi Angela , Spitaels Jan , Mina Andrea Joselin Morales , Garcia-Sastre Adolfo 
Published: January 2023

Abstract
Conventional influenza vaccines aim at the induction of virus-neutralizing antibodies. Influenza viruses can escape neutralization by antibodies through antigenic drift or shift or because antibody levels diminish. We wondered to what extent infection-permissive immunity provided by a trivalent inactivated influenza virus vaccine (TIV) could modulate disease and virus-induced host immune responses after homologous H1N1 infection. We first focused on alveolar macrophages, cells that are transiently lost during influenza infection in the mouse-influenza challenge model. Later we focused on how vaccine-induced immunity modulates induction of cross-reactive CD8+ T cells by virus infection. TIV vaccination did not result in detectable HI titers but correlated with lower viral lung titers and faster recovery after challlenge. Alveolar macrophages were abolished at 7dpi in negative control mice, but not in TIV-vaccinated mice. TIV vaccination allowed the induction but also affected levels of cross-reactive NP-specific CD8+ T cell responses, which correlated with protection against heterosubtypic H3N2 virus. The effect of TIV vaccination on TCR Vbeta-region bias of CD8+ T cells after secondary challenge with H3N2 virus was also investigated.
These results suggest that suboptimal vaccination with conventional influenza vaccines may still positively modulate disease outcome, thereby allowing induction of heterosubtypic immunity by virus infection.
Lung extracellular matrix changes mediated by ADAMTS-4 modulate immune responses to influenza A infection
Authors: Boyd David F , Guo Xizhi , Allen Emma Kaitlynn , Thomas Paul Glyndwr 
Published: January 2023

Abstract
The lung extracellular matrix (ECM) undergoes dramatic changes during and after respiratory viral infection. Matrix proteases, including members of matrix metalloproteinases (MMPs) and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) gene families, play a critical role in remodeling the ECM following tissue damage. Alterations in the ECM feed into immunological pathways, which subsequently regulate repair and regeneration. The mechanisms that regulate matrix proteases and the effect of lung ECM changes on immune responses to viral infection have not been well characterized. We previously found that ADAMTS-4 was upregulated in the lung within 3 days after influenza infection and that genetic knockout of ADAMTS-4 resulted in improved survival following infection in mice. Using quantitative PCR, we determined the transcriptional levels of 96 ECM-related genes in lung homogenates from ADAMTS-4 −/− and +/+ mice during a 15-day infection time course. At early time points, lungs from ADAMTS-4 −/− mice exhibited lower expression of inflammatory cytokines, including IL-6 and IL-1β, but higher expression of several ECM remodeling enzymes, including neutrophil elastase and MMP-13. Flow cytometric analysis of immune cell populations from lungs revealed altered neutrophil and T cell kinetics between ADAMTS-4 −/− and +/+ mice over the course of influenza infection. Lungs from ADAMTS-4 −/− mice exhibited higher numbers of neutrophils at 3 dpi and a higher percentage of IFNγ-producing CD4+ and CD8+ T cells at 6 dpi, but lower numbers of these cells by 12 dpi. These results suggest that ADAMTS-4-mediated alterations of the lung ECM modulate immune responses to influenza infection and may contribute to immunopathology.
PD-1 expression on Foxp3+ Treg cells modulates CD8+ T cell function in prostatic tumor microenvironment
Authors: Kumar Sanjay , Malik Shalie , Singh Udai P. , Ponnazhagan Selvarangan , Scissum-Gunn Karyn , Manne Upender , Mishra Manoj K. 
Published: January 2023

Abstract
Regulatory T (Treg) cells act as terminators of T cell immune response during prostate cancer progression and development. However, their role and immunosuppressive mechanism(s) in context to programmed death 1 (PD-1) is not completely understood. The present investigation is aimed to determine the role of PD-1 on Treg cells and their impact on CD8+ T cell function in prostatic tumor microenvironment using transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMP C1, C2 and C3) as a model system. To execute the above aim, tumor induction studies were performed. Briefly, the C57BL/6 mice were administered with serial log concentrations of TRAMP (C1-3) cells. Interestingly, the TRAMP-C3 cells do not form tumor, however, TRAMP-C1 and TRAMP-C2 cells do form tumor. After tumor development, mice were sacrificed by cervical dislocation; tumor, lung, spleen, and draining lymph nodes were harvested when the tumor size reached approximately 20mm. Single cell suspensions were prepared from different organs, cells were then stained with specific antibodies, and flow analyzed for the expression of different immune markers. Our preliminary findings demonstrated that PD-1 expression on Foxp3+ Treg cells displayed greater suppressive capacity against CD8+ T cell function in tumor, lung, spleen, and draining lymph node when compared to the control. More importantly, Foxp3+ Treg(high) PD-1(high) interaction with PDL-1 induced immunosuppression by blocking CD8+ T cells function in prostatic tumor microenvironment. In conclusion, Foxp3+ Treg(high), PD-1(high), and CD8+(low) T cells may enhance tumor progression; thus, targeting the PD-1 on Treg cells may be a possible therapy to treat prostate cancer.
Secondary iTreg generation has a major impact on the tumor-infiltrating Treg population in cancer patients.
Authors: Xydia Maria , Ruggiero Eliana , Domschke Christof , Mastitskaya Svetlana , Pritsch Maria , Schmidt Manfred , von Kalle Christof , Schütz Florian , Beckhove Philipp 
Published: January 2023

Abstract
CD4+ regulatory T cells (Treg) have a detrimental effect in cancer-immunity, as they suppress tumor-specific effector T cells (Teff) hindering tumor eradication. Indeed, increased Treg numbers in various cancer types, including breast cancer, correlate with poor patient prognosis. Based on animal studies, Treg enrichment may result from the expansion of thymic natural Treg but also through the conversion of conventional T cells (Tconv) into induced Treg (iTreg) under tumor-suppressive conditions. However, little is known about tumor-specific iTreg generation in humans and its impact on the TCR repertoire of peripheral Treg.
Therefore, we compared the TCRβ repertoire of total Treg and tumor-reactive Teff or total Tconv from peripheral blood of breast cancer patients or healthy individuals, as negative control, for the identification of overlapping TCRs, representing iTreg. In addition, using high-throughput single-cell transcriptome sequencing combined with TCRαβ characterization we analyze the functional profile of individual Treg and Tconv clones, in order to elucidate their specific role in anti-tumor immunity in humans.
No major TCR overlap was observed between Treg and tumor-reactive Teff or total Tconv in peripheral blood of patients and healthy individuals, arguing against the existence of tumor-specific iTreg in the circulation. Nevertheless, within the tumor Treg and Tconv shared dominant highly-expanded clones, representing 10–65% of the tumor-infiltrating Treg population but with no effect in peripheral blood.
Taken together, our data suggest that intratumoral secondary Treg conversion from dominant Tconv clones may have a major impact on the tumor-infiltrating but not on the circulating Treg population.
Regulation of Myeloid Derived Suppressor Cell (MDSC) dynamics by T regulatory cells
Authors: Tanwar Shalini , Shevach Ethan M 
Published: January 2023

Abstract
Multiple sclerosis is an inflammatory demyelinating autoimmune disorder affecting the central nervous system whose severity is reduced using immune suppressive drugs. Therapeutic intervention with interferon-b reduces disease exacerbations and delays relapses. The receptor for type 1 interferon, IFNAR, is present on virtually all cell types making it difficult to dissect the mechanisms involved. We generated mice with a conditional deletion (cKO) of IFNAR in Treg cells (IFNARfl/flFoxp3cre). cKO mice developed severe EAE with an earlier onset than control mice. The activation status and effector cytokine production of CD4+ and CD8+ T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase. Treg activation and expansion were also similar in WT and cKO mice. However, we noted a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice while equivalent numbers of MDSCs were present in bone marrow and spleen of WT and cKO mice. IFNARfl/flLysMcre mice do not show a similar reduction in MDSC number indicating that the enhanced disease severity in the cKO mice is dependent on IFNAR signaling on Treg cells. CD4+ T cells from cKO mice were found to be defective in chemokine secretion suggesting that IFNAR signaling on Treg modulates the capacity of CD4+ T cells to secrete MDSC recruiting chemokines during the priming phase. While modulation of Treg number and function by MDSCs has been documented, this study is one of the first to demonstrate that Treg may modulate MDSC homing and raises the possibility of a novel role for Treg cells in regulating the kinetics of MDSC recruitment during inflammatory conditions.
Supported by the Division of Intramural Research NIAID.
Identification of a suppressor of autoimmune phenotype that affects deoxynucleotide synthesis in T cells
Authors: Bolland Silvia , Sule Gautam , Scott Bethany , Tarasenko Tatyana 
Published: January 2023

Abstract
FcγRIIB-deficient mice represent a well-characterized animal model of systemic lupus erythematosus. They develop spontaneous anti-nuclear antibodies (ANA) and fatal glomerulonephritis when on the C57BL/6 (B6) background while the same mutation on the BALB/c background is phenotypically benign, indicating differences in lupus susceptibility between the BALB/c and B6 strains. We mapped the BALB/c derived protection to a 151KB genomic fragment on chromosome 12. Insertion of this fragment in transgenic form (A12Tg) results in protection from lupus disease. Mixed bone marrow reconstitution experiments pointed to a T cell intrinsic effect of the protective gene in the BALB/c A12 interval. This region contains a single gene, Rrm1, which encodes for a subunit of the ribonucleotide reductase responsible for the synthesis of deoxiribonucleotides. We hypothesize that reduced levels of this enzyme affect the ability of T cell to expand upon activation and that is why allelic differences in Rrm2 expression can alter tolerance in mouse models of lupus.
‘Interleukin-7 production by dendritics cells is critical for negative selection of CD4+ lymphocytes in the thymus’
Authors: Moutuou Moutuaata Mohamed , Thiant Stéphanie , Leboeuf Dominique , Guimond Martin 
Published: January 2023

Abstract

Introduction
IL-7 plays a crucial role in thymopoiesis, this cytokine is mainly expressed by thymic epithelial stroma cells and dendritics cells (DCs). During thymopoiesis, thymocytes undergo positive and negative selection which ensures the generation of a functional T-cell repertoire. In the thymus, Antigen presenting cells including medullary thymic epithelial cells (mTEC) and DCs, express a variety of self-peptides that contribute to purge the repertoire of self-reactive thymocytes. Studies have indicated that co-stimulation through cell surface molecules and cytokine mediated by DCs is important during negative selection. Given that DCs produce IL-7 and IL-7 can modulate TCR signaling, we hypothesized that IL-7 production by DCs might increases TCR sensitivity and modulates negative selection.

Objective
We limited IL-7 production to thymic epithelial cells by engineering chimeric Rag−/− mice transplanted with hematopoietic stem cells from IL-7−/− mice. Following bone marrow (BM) transplantation, control mice (C57BL/6 BM in Rag−/−) remains healthy whereas recipients of IL-7−/− BM developed signs of illness and dies within 5–6 weeks. Adoptive transfer of CD4+ but not CD8+ T cells recapitulated the disease host. We confirmed a defect in negative selection by observing the production of autoreactive anti-HY T cells TCR transgenic Marilyn male mice receiving IL-7−/− BM.

Conclusion
Our data identified an unsuspected role of DCs-derived IL-7 in negative selection of CD4+ T cells.
T regulatory cells follow CXCL10 to suppress T effector cells through a contact-dependent mechanism in the skin during vitiligo
Authors: Essien Kingsley Imeh , Richmond Jillian M , Strassner James P , Harris John E 
Published: January 2023

Abstract
Vitiligo is an autoimmune disease of the skin driven by CD8+ T effector cells (Teffs) that infiltrate the epidermis to kill melanocytes, resulting in visible white spots. To investigate the role of T regulatory cells (Tregs) during vitiligo we depleted Tregs in our mouse model with CD4 depleting antibody or diphtheria toxin-treated Foxp3-DTR mice and saw increased disease (p&lt;0.0001 and p&lt;0.02, respectively) and increased Teff skin infiltration, suggesting that Tregs suppress Teffs during vitiligo. We investigated the kinetics of Treg and Teff migration to the skin in our mouse model and saw that both cell types accumulate in a similar pattern, suggesting that Tregs may follow the same signals that recruit Teffs to the skin. Previous studies revealed that CXCL10, which is upregulated in human patients as well as in our mouse model of disease, is primarily expressed in the epidermis and necessary for the migration of CXCR3+Teffs to the epidermis. Using flow cytometry we saw that both mouse and human Tregs in the skin express CXCR3 during vitiligo and confocal microscopy revealed that mouse Tregs co-localize with CXCL10 expression in the skin during vitiligo. Using confocal microscopy, we observed that Tregs directly contact Teffs in mouse skin, suggesting that Tregs may use contact-dependent mechanisms of suppression in the skin. We found similar interactions in human skin and hypothesize that Tregs follow CXCL10 to localize with Teffs in the epidermis where they suppress Teffs through a contact-dependent mechanism.
A novel method to classify subpopulations in murine spleen and blood using multiparametric imaging flow cytometry.
Authors: Kong Raymond K , Zhou Weiyang , Venkatachalam Vidya , McCann Kelly , Pugsley Haley Renee , Friend Sherree , Morrissey Philip 
Published: January 2023

Abstract
Being able to identify the lymphocytes, monocytes, and neutrophils (granuolcytes) subpopulations in murine spleen and peripheral blood is an important step of the analysis of the immune system. Conventionally, this task is accomplished by performing immunofluorescence staining of specific cell surface markers. However, given the distinct morphology of each of these subpopulations as well as the cell imageries obtained using the Image Stream technology, we attempt to identify 3cell types in the spleen and peripheral blood samples of C57BL/6 and BALB/c mice based solely on the Bright Field (BF), Side Scatter (SSC) and nuclear images without using any specific markers for the cell types. We will then compare the results obtained using this novel method with that obtained using immunofluorescence. We hope that the results will serve to both validate our methodology and highlight the value offered by this objective, automated, and quantitative approach towards other murine immune cell analysis, particularly in those situations where immunofluorescence based subpopulation detections are either unfeasible(due to fluorochrome conflicts) or impractical (due to high sample sizes).
Prime and Target Immunization Protects Against Liver-Stage Malaria
Authors: Gola Anita , Walters Adam A , Uderhardt Stefan , Salman Ahmed M , Halbroth Benedict R , Khan Shahid M , Janse Chris J , Germain Ronald N , Spencer Alexandra J , Hill Adrian VS 
Published: January 2023

Abstract
A highly effective vaccine against malaria is urgently needed, with leading vaccination strategies targeting primarily the pre-erythrocytic liver stages of the Plasmodium falciparum lifecycle. Malaria antigen specific CD8+ T-cells to are known to be protective, with heterologous prime-boost viral vector immunization being an effective method of induction. Non-replicating viral vectored vaccines have shown a remarkable capacity to induce systemic CD8+ T-cell responses in animals and humans. To date, the greatest immunogenicity has been obtained through a heterologous prime boost regimen, where vaccination with an adenoviral vector is followed 8 weeks later by a Modified Vaccinia Ankara virus (MVA) boost. A novel vaccine strategy aimed at priming CD8+ T-cells in the periphery and subsequently targeting them to hepatic tissue with protein loaded poly(lactic-co-glycolic acid) nanoparticles or recombinant viral vectors administered by specific immunization routes was developed. Durable Ag-specific CD8+ T-cells exhibiting a phenotype of tissue-resident memory (TRM) T-cells were generated in the liver, with a ten-fold increase over the conventional heterologous vector regime. Importantly, in a P. berghei sporozoite challenge model of liver-stage malaria, this strategy was found to result in unprecedented sterile protection across several clinically relevant antigens and mouse strains. This prime and target immunization strategy for malaria may provide a general approach for prevention or immunotherapy against pathogens that infect the liver.
Suppression of vaccination-induced antigen-specific regulatory T cells enhances the antiviral immunity against influenza virus infection
Authors: Lin Pin-Hung , Yang Hung-Chih 
Published: January 2023

Abstract
T cell immunity targeting the conserved epitopes of influenza virus has the potential to provide cross-protection against distinctly-related strains. Peptide vaccines are an ideal strategy to induce specific antiviral T cell immunity, but subimmunogenic stimulation by peptide vaccines tend to induce regulatory T (Treg) cells. However, it remains unclear about the roles of vaccine-induced antigen-specific Treg cells in vivo. Here, we aimed to investigate how vaccine-induced antigen-specific Treg cells respond during acute influenza virus infection, and the effects of adjuvants on them. By adoptive transfer experiments with OT-II TCR transgenic T cells, we found that the OVA OT-II peptide vaccine induced Treg cells and secondary vaccination further expanded them. Infection with influenza virus containing the OVA OT-II peptide also drove the expansion of pre-existing vaccine-induced Treg cells. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells enhanced the antiviral immunity. Vaccination combined with adjuvants, especially with CpG, suppressed the development of vaccine-induced antigen-specific Treg cells. Finally, CpG-adjuvanted OVA protein or whole inactivated influenza vaccine by the subcutaneous-prime-intranasal-boost strategy reduced the ratio of antigen-specific Treg cells in lung and protected mice from the heterosubtypic influenza infection. In conclusion, unadjuvanted peptide vaccines promoted antigen-specific Treg cells, which were further expanded upon acute influenza infection. The CpG adjuvant restricted the development of vaccine-induced antigen-specific Treg cells, and enhanced the antiviral T cell immunity against heterosubtypic influenza infection.
Model specific role of B cell-intrinsic IFNαR signaling in promoting spontaneous germinal centers and autoimmunity
Authors: Domeier Phillip P , Chodisetti Sathi Babu , Soni Chetna , Schell Stephanie L , Fasnacht Melinda J , Imamura Yuka , Salzberg Anna , Rahman Ziaur 
Published: January 2023

Abstract
In systemic lupus erythematosus (SLE), germinal centers can form spontaneously (Spt-GCs) in the absence of foreign antigen and drive high-affinity autoantibody (autoAb) production. Overexpression of Type 1 interferon (IFNα) accelerates autoimmunity and alters B cell selection in certain SLE mouse models, but in another model, B cell intrinsic IFNαR signaling is shown to be dispensable for autoimmune GC response and autoimmunity. Using B6.Sle1b autoimmune mice derived from the NZM2410 SLE mouse model, we show here that IFNαR signaling is not required for Spt-GC formation but is important for elevated Spt-GC response and autoreactive B cell selection into AFCs. IFNα receptor1 deficient B6.Sle1b mice (B6.Sle1b.IFNαR1−/−) have lower Spt-GC and Tfh responses, reduced CD86 expression on B cells and diminished autoAb titers as compared to B6.Sle1b mice. We also observe lower Ca2+ flux in B cells deficient in IFNα receptor compared to control B cells upon BCR cross-linking in vitro. Consistently, we find that B cell-intrinsic IFNαR signaling promotes differentiation of Sle1b-expressing DNA-reactive B cells into GC B cells. RNA sequencing studies show that B6.Sle1b and B6.Sle1b.IFNαR1−/− GC B cells have distinct transcriptional profiles that are associated with proliferation, cell survival, and antigen presentation pathways. Compared to B6.Sle1b control, B6.Sle1b.IFNαR1−/− B cells fail to form stable conjugates with T cells in vitro and GC B cells express reduced levels of ICOS-ligand in vivo, suggesting B6.Sle1b.IFNαR1−/− B cells may not acquire adequate T cell help. These data reveal novel information about the model specific role of B cell-intrinsic IFNαR signaling in the regulation of Spt-GCs and autoimmunity.