bluuebunny/crossref_metadata_2025_split huggingface dataset:
Location of immunization and interferon-γ are central to induction of salivary gland dysfunction in Ro60 peptide immunized model of Sjögren's syndrome (101.25)
Authors: Yin Hongen , Vosters Jelle , Roescher Nienke , D’Souza Anil , Kurien Biji , Tak Paul , Chiorini John 
Published: January 2023

Abstract
Introduction: Anti-Ro antibodies can be found in the serum of the majority of patients with sjögren's syndrome (SS), which is a chronic autoimmune epithelitis. Immunization with a 60-kDa Ro peptide (Ro60) has been shown to induce SS in mice. The aim of this study was to investigate the mechanism associated with loss of gland activity and optimal conditions and factors involved in salivary gland (SG) dysfunction in this animal model. Methods: Ro60 peptide immunization (either convention or multiple antigenic peptide (MAP)-Ro60) was tested in two strains of mice with or without secondary adjuvant and in different injection sites. Each group of mice was tested for loss of SG function, SG lymphocytic infiltration, anti-Ro and anti-La antibody formation, and cytokine production in cultured cells or homogenized SG extracts. Results: Ro60 peptide immunization in the abdominal area of female Balb/c mice led to impaired SG function, which corresponded with increased Th1 cytokines (IFN-γ and IL-12). Changing the immunization conditions to MAP-Ro60 in the abdominal area also led to impaired SG function in SJL/J mice. As was seen in the Balb/c mice, increased IFN-γ corresponded with SG dysfunction. Conclusions: Effective induction of SG dysfunction after Ro60 peptide immunization depends on the site of injection. The mechanism of action of Ro60 peptide immunization appears to involve an increase in Th1 cytokines, resulting in the induction of SG dysfunction.
CD45ROhighCD57+CD8high T cells in primary biliary cirrhosis (101.4)
Authors: Tsuda Masanobu , Ambrosini Yoko , Moritoki Yuki , Yoshida Katsunori , Zhang Weici , Yang Guo-Xiang , Ando Yugo , Rong Guanghua , Nakatani Toshio , Bowlus Christopher , Ansari Aftab , Lian Zhe-Xiong , Gershwin M. Eric 
Published: January 2023

Abstract
Primary biliary cirrhosis (PBC) is a female predominant organ specific autoimmune disease with specific destruction of intrahepatic small biliary epithelial cells (BECs). Patients develop a multilineage response to the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody as well as autoreactive CD4 and CD8 T cell responses. Recent data from murine PBC models have suggested that liver-infiltrating CD8 T cells play a critical role in biliary destruction in PBC. Many studies suggest the augmented cytotoxicity of CD57+CD8 T lymphocytes. Therefore, we have studied the frequencies and phenotypic characterization of CD8highCD57+ T lymphocyte components in both patients with PBC and age matched controls. Our data indicate that CD45ROhighCD57+CD8high T lymphocytes from PBC patients, but not controls, have significant phenotypic alterations, including increased expression α4β7high and reduced expression of annexin V after TCR stimulation. Our data also indicate that patient CD45ROhighCD57+CD8high T cells express higher granzyme A, B, perforin, CCR5 and α4β7, reduced expression of CCR7 than other CD8high T cells. Furthermore, IFN-γ and IL-5 productions by CD57+CD8high T lymphocytes upon in vitro TCR stimulation are increased in PBC patients. In conclusion, our data demonstrate that CD45ROhighCD57+CD8high T cells are a subset of cytotoxic memory cells which play a critical role in the chronic and progressive destruction of BECs in PBC.
Functional expression of HLA-E by human oligodendrocytes (101.40)
Authors: Zaguia Fatma , Antel Jack , Saikali Philippe , Arbour Nathalie 
Published: January 2023

Abstract
Immune cells infiltrating the central nervous system (CNS) of Multiple Sclerosis (MS) patients contribute to the destruction of oligodendrocytes. We aim at characterizing mechanisms implicated in such CNS damage. HLA-E, a non-classical MHC class I molecule, is recognized by either the NKG2C or NKG2A receptors expressed on subsets of T cells and NK cells. While NKG2C is an activating receptor, NKG2A is described as an inhibitory receptor. Activated human immune effectors including NK and T cells can kill human oligodendrocytes in vitro, yet whether HLA-E could modulate such cytotoxicity is unresolved. We observed that human adult oligodendrocytes express basal HLA-E levels, which are upregulated upon pro-inflammatory cytokine treatments, mimicking the inflamed CNS observed in MS lesions. We performed in vitro functional assays using activated immune cells bearing either the NKG2A (NK cells) or NKG2C (CD4 T cells) receptor co-cultured with human oligodendrocytes. We observed that addition of blocking antibodies specific for NKG2A on NK cells increased the killing of oligodendrocytes compared to an isotype control. In contrast, we detected a decreased cytotoxicity against oligodendrocytes when we block the activating receptor NKG2C on a subset of CD56-positive CD4 T cells, which we previously identified as carrying cytotoxic properties. Our results support that human oligodendrocytes modulate via the expression of HLA-E, cytotoxic attacks mediated by several immune effectors.
Sequential effects of IL-21 and IL-17 to regulate spleen CXCR5+ follicular T helper cells in autoimmune BXD2 mice (101.44)
Authors: Ding Yanna , Hsu Hui-Chen , Wu Qi , Yang Pingar , Mountz John 
Published: January 2023

Abstract
CXCR5+ follicular T helper (Tfh) cells locate in the light zone (LZ) of germinal centers (GCs) to help differentiation of antibody producing B cells. Both IL-17 and IL-21 have been associated with the development of GCs but their effects on Tfh have not been clear. Autoimmune BXD2 mice developed spontaneous GCs and displayed increased number of Tfh in the spleen. In BXD2-Il21-/- or BXD2-Il17ra-/- mice, there were significantly reduced PNA+Fas+ GC B cells in the spleen and autoantibody titers in sera. This is not exclusively related to Tfh development since the percentage of CXCR5+ICOS+ Tfhs is 2-fold lower in BXD2-Il21-/- but is 1.5-fold higher in BXD2-Il17ra-/- mice compared to wild type. Confocal images, however, showed dramatically diminished CD4 T cells in GC LZ of BXD2-Il17ra-/- spleen. In vitro treatment of CD4 T cells with IL-21 increased the percent of CXCR5+ICOS+ Tfhs and the expression of IL17R on them. qRT-PCR confirmed that IL-21 treatment increased the expression of Cxcr5, Icos and Il21 on CD4 T cells. In contrast, IL-17 treatment increased Rgs16 but decreased Cxcr5 and diminished CXCL13-mediated chemotaxis on CD4 T cells. Our study suggests that IL-21 and IL-17 act sequentially on Tfhs in BXD2 mice. IL-21 first promotes differentiation of Tfhs and prepared these cells for IL17 stimulation by upregulating IL-17R. Subsequently, IL-17 is required to upregulated the expression of Rgs16 and stabilizes Tfh in GC LZ to promote spontaneous development of GCs.
Development of a high throughput cell migration assay using the SRU BIND reader (102.13)
Authors: McAllister Kathryn , Abodeely Marla , Shamah Steven , Zhang Qin 
Published: January 2023

Abstract
The chemotactic ability of non-adherent cells can be assessed by a variety of techniques, but is typically performed using transwell plates in which a chemoattractant induces the migration of cells through a porous membrane. Throughput and robustness are limitations to this assay format. The aim of this study was to develop a novel, higher throughput, robust, cell migration assay using the human monocytic derived U937 cell line and the SRU BIND® label free detection platform. C5a is a powerful chemoattractant which is generated by all 3 pathways of the complement system. C5a binds to the C5a receptor which is expressed on many different inflammatory cell types, including neutrophils, monocytes, and macrophages, and it mediates migration of these cells under pro-inflammatory conditions. Differentiated U937 cells express the C5a receptor and migration of these cells can be induced by C5a. These cells were seeded on a 384-well BIND® biosensor and following an attachment period, collagen was added and allowed to form a solidified layer. Following the addition of C5a the cells migrated up off the biosensor toward the chemoattractant stimulus producing a bell shaped concentration response curve, as typically observed for C5a in classical chemotaxis assays. The response was inhibited by reference C5a receptor antagonists. This assay format could also be developed to evaluate the migratory ability of primary cells such as monocytes or neutrophils to inflammatory chemoattractants.
ECM1 controls Th2 cell egress from lymph nodes through re-expression of S1P1 (102.3)
Authors: Sun Bing , Li Zhenghu , Zhang Yuan 
Published: January 2023

Abstract
The T helper 2 (Th2) subset of T cell is critically involved in allergy and asthma. In this study, we demonstrate that the Extra-Cellular Matrix protein 1 (ECM1), a secreted protein, is highly and selectively expressed in Th2 cells. ECM1 deficiency caused impaired Th2 responses and reduced allergic airway inflammation in vivo. Functional analysis demonstrated that although Th2 polarization was unimpaired, ECM1 deficient Th2 (but not Th1) cells exhibited a defect in migration and were retained in peripheral lymphoid organs. This was associated with reduced expression of the transcription factor klf2 and its downstream target, the chemokine receptor S1P1 and could be corrected by retroviral transduction of individual members of the pathway. We also found that ECM1 can directly bind to IL-2 receptor to inhibit IL-2 signaling and activate S1P1 expression. Our data identify a novel function of ECM1 in regulating Th2 cell migration through controlling of klf2 and S1P1 expression.
TNF-α produced by inflammatory DCs as a molecular switch in Th17/Th2 and neutrophilic/eosinophilic responses during persistent fungal infection (103.2)
Authors: Fei Mingjian , Bhatia Shikha , Oriss Timothy , Yarlagadda Manohar , Khare Anupriya , Akira Shizuo , Iwakura Yoichiro , Ray Prabir , Kolls Jay , Ray Anuradha 
Published: January 2023

Abstract
Aspergillus fumigatus is associated with allergic bronchopulmonary aspergillosis, a pulmonary allergic disorder, in which neutrophilia predicts a poor outcome. In our efforts to recapitulate fungus-induced airway neutrophilia in the allergic setting, we found that similar exposure to the fungus resulted in a neutrophil-dominated response in BALB/c mice but an eosinophil-biased response in C57BL/6 mice. By performing a comparative study, we identified TNF-α as the key mediator that skewed the response towards neutrophilia but away from eosinophilia. Between the two strains, TNF-αhigh CD11b+ Ly6C+ DCs were more abundant in the lungs of WT BALB/c mice which was compromised in MyD88-/-, dectin-1-/- and TNF-α-/- mice. As compared to TNF-αhigh Balb/c-DCs, TNF-αlow C57BL/6-DCs contained more NF-B p50 homodimers as strong repressors of TNF-α transcription. Lower TNF-α accounted for lower TLR2 levels on C57BL/6 DCs impairing collaboration between TLR2 and Dectin-1 in augmenting TNF-α via a positive feedback loop. Functionally, in Balb/c mice, the high level of TNF-α enhanced Th17 responses and in collaboration with IL-17A upregulated the neutrophil chemoattractants KC and MIP-2. Conversely, the lungs of C57BL/6 or TNF-α-/- mice showed higher IL-5 levels and therefore an eosinophil-rich response. Our study for the first time highlights a central role of TNF-α as a molecular switch that regulates the neutrophil/eosinophil balance in airway inflammation.
Role of specific dendritic cells in inducing Tregs in response to inhaled allergen. (103.5)
Authors: Khare Anupriya , Qi Zengbiao , Fei Mingjian , Ray Prabir , Ray Anuradha 
Published: January 2023

Abstract
Foxp3+ Regulatory T cells (Treg), both naturally occurring thymus-derived nTregs and peripherally induced Foxp3+ induced Tregs (iTreg), play a critical role in suppressing immune responses to self as well as external antigens, ensuring protection from autoimmune and allergic diseases such as asthma. Recent investigations have established a role for iTregs in the regulation of chronic allergic lung inflammation. However, the cellular and molecular mechanisms mediating induction of Tregs in the lungs are still unclear. In this study, we explored the role of dendritic cells (DCs) in Treg induction in response to inhaled allergen. Using an adoptive transfer model we demonstrate that exposure to low doses of allergen results in the induction of Foxp3+ Tregs (tolerance) in the lungs which requires the presence of CD11c+ DCs. Amongst the various resident DC subsets in the lungs, CD103+ lung DCs were the most potent inducers of iTregs. The tolerogenic property of the CD103+ DCs was compromised under inflammatory conditions and the DCs did not induce Tregs as efficiently. Finally, the induction of Tregs by CD103+ DCs was dependent on retinoic acid and TGF-β and was promoted in the absence of IL-4 signaling. Taken together, we show that despite the presence of multiple DC subsets in the lung, CD103+ DCs selectively mediate airway tolerance to inhaled allergens. Thus, strategies to improve the function of CD103+ DCs in the lung would help ameliorate allergic airways disease.
The protective role of TLR6 during experimental fungal asthma is mediated by IL-23 and IL-17A. (103.6)
Authors: Moreira Ana , Cavassani Karen , Hullinger Rikki , Knight Darryl , Kunkel Steven , Uematsu Satoshi , Akira Shizuo , Hogaboam Cory 
Published: January 2023

Abstract
Toll-like receptors (TLRs) mediate pathogen recognition in the respiratory system, but TLR activation has both beneficial and deleterious effects during asthma. Clinical data demonstrates that TLR6 is an example of a pattern recognition receptor that exerts protective effects in clinical asthma. To explore the mechanism through which TLR6 expression by immune and inflammatory cells mediates this effect, we investigated its role in a murine model of Aspergillus fumigatus-induced chronic asthma. TLR6-/- mice with fungal asthma exhibited significantly increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole lung levels of IL-23 and IL-17 were significantly lower in TLR6-/- versus WT asthmatic mice. TLR6-/- DCs generated significantly less IL-23 upon activation with either lipopolysaccharide or zymosan. Impaired IL-23 generation in TLR6-/- mice also corresponded with significantly lower dectin-1 expression and Th17 expansion both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic TLR6-/- mice in vivo restored IL-17A production and significantly reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with untreated asthmatic TLR6-/- mice. Together, we demonstrate that TLR6 activation is critical for IL-23 and Th17, and both regulate the allergic inflammatory response during fungal asthma.
Co-expression of CD8α and CD8β defines a subset of tolerogenic plasmacytoid dendritic cells able to induce the differentiation of Foxp3+ regulatory T cells. (103.9)
Authors: Lombardi Vincent , Szely Natacha , Akbari Omid 
Published: January 2023

Abstract
Recent findings suggest that different subsets of dendritic cells (DCs) control the balance between protection against pathogens and tolerance to innocuous or self antigens. Latest data propose that plasmacytoid DCs (pDCs) act as antigen-presenting cells during adaptive immune responses and promote peripheral tolerance. In this study, we demonstrate for the first time that mouse pDCs can be segregated into three distinct populations according to their surface expression of CD8α alone or combined with CD8β. These subsets not only differ in phenotype but are also functionally distinct since CD8α+ CD8β− and CD8α+ CD8β+ pDCs are more potent inducers of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) compared to CD8α− CD8β− pDCs. Our results indicate that, in a mouse model of allergic asthma, adoptive transfer of CD8α+ CD8β− or CD8α+ CD8β+ prevents the development of airway hyperreactivity. By comparing the gene expression profile of the three subsets of pDCs described in this study, we established that the expression of CD98hc, a receptor for the Galectin-3, was significantly up-regulated in both CD8α+ CD8β− and CD8α+ CD8β+ subsets. Adding Galectin-3 to sorted CD8α+ CD8β− or CD8α+ CD8β+ pDCs in vitro, enhances the conversion of naive CD4+ T cells into Tregs. Thus, our data unveil for the first time, subsets of pDCs with the capacity to induce regulatory functions that may contribute to the establishment of immunological tolerance.
Determining the role of basal NF-κB in the survival of quiescent naïve T cells (104.14)
Authors: Miller Michelle , Mashayekhi Mona , Chen Luqiu , Liu Xindong , Michelotti Monica , Tramontini Nicole , Powers Sarah , Zhu Xiaoping , Alegre Maria-Luisa , Molinero Luciana 
Published: January 2023

Abstract
NF-κB is an essential transcription factor for the survival of T cells following antigen stimulation, but whether it plays a role in maintaining the survival of unstimulated naïve T cells is not known. We have detected basal NF-κB activity in naïve quiescent T cells and investigated whether it is important in cell survival in the absence of T cell activation. NF-κB-impaired naïve CD4+ T cells showed decreased lifespan in vivo. IL-7 has been shown to be important for naïve T cell survival prompting investigation into whether basal NF-κB activity could regulate IL-7/IL-7R signaling. Our results indicate that NF-κB-impaired naïve T cells are resistant to the pro-survival effects of IL-7 in vitro, and that these T cells express less surface IL-7Rα than wild type T cells. To determine whether NF-κB could regulate IL-7Rα expression by transcription, a putative NF-κB-binding site 3.5 kB upstream of the IL7r translational start site was tested. Nuclear NF-κB from naïve T cells was capable of binding an oligonucleotide probe containing this sequence, as determined by EMSA. A ChIP assay confirmed that the p50 and p65 subunits of NF-κB bound this region in live wild type but not NF-κB-impaired naïve T cells. Finally, re-expression of IL-7Rα after IL-7-mediated degradation was RNA polymerase- and NF-κB-dependent. Together, these results support the idea that basal NF-κB activity plays a role in the survival of quiescent naïve T cells by controlling transcription of the IL7r gene.
Virus-specific T cell clonal expansions can limit recall responses to secondary respiratory virus infections (104.4)
Authors: Connor Lisa , Ryan Lynn , Kohlmeier Jacob , Cookenham Tres , Roberts Alan , Quinn Adam , Woodland David 
Published: January 2023

Abstract
Respiratory virus infections are a major health problem in the elderly. This is due to declining immune responsiveness in the elderly and the development of CD8+ T cell clonal expansions (TCE) that perturb the memory T cell pool. We recently showed that TCE can arise over time from memory CD8+ T cells established by an acute respiratory viral infection. Virus-specific TCE are phenotypically identical to conventional memory cells and do not express the characteristics of exhausted cells. Since TCE can dominate the memory T cell pool, it is essential to determine the rate at which they develop, and their ability to mount a recall response to secondary pathogen challenge in vivo. In the current study, we developed an assay to detect developing TCE in a cohort of mice following Sendai virus infection and found a progressive increase in the appearance of TCE within the first year following infection. Using a dual adoptive transfer approach to address the recall potential of virus-specific TCE, we demonstrate that the majority of TCE examined are poorly responsive to a secondary infection. Taken together, the data suggest that the development of TCE is a common occurrence due to the progressive dysregulation of the virus-specific memory T cell pool with age, and many TCE are profoundly defective in their ability to mediate recall responses.
An influence of galectin-9/Tim-3 interaction on Herpes simplex virus-1 latency (105.14)
Authors: Jagadeesh Reddy Pradeep Babu , Sehrawat Sharvan , Suryawanshi Amol , Rajasagi Naveen , Rouse Barry 
Published: January 2023

Abstract
In this report, we show that the majority of CD8+T cells in the trigeminal ganglion (TG) of mice ocularly infected with HSV-1 express Tim-3, a molecule that delivers negative signals to CD8+T cells when it engages its ligand, Galectin 9 (Gal-9). Curiously Gal-9 glycoprotein is also up regulated in the TG both during the time when replicating virus is present as well during early viral latency. Accordingly it is conceivable that the efficiency of ganglionic CD8+T cell function could be influenced by Gal-9/Tim-3 interaction. In support of this we show that the activity of peptide stimulated CD8+T cells recovered from the TG of WT mice produced less IFN-γ, TNF-α and Granzyme B molecules in comparison to TG CD8+T cells of Gal-9KO mice. Differences in the number of productively and latently infected neuronal cells were also evident between WT and Gal-9KO mice. In vitro studies demonstrated that TG cell cultures of WT HSV-1 infected mice exposed to recombinant Gal-9 in the latent phase caused apoptosis of some CD8+T cells and induce viral reactivation. Our results demonstrate that the host homeostatic mechanism mediated by Gal-9/Tim-3 interaction on CD8+T cells can influence the outcome of latent HSV-1 infection. Neuronal cell function is likely to be preserved when host Gal-9 levels are low, since inhibitory effects on latency controlling CD8+T cells will be minimal.
The role of GPI-anchored proteins in the preferential binding and infection of poxviruses with primary human monocytes (105.19)
Authors: Byrd Daniel , Hu Ningjie , Amet Tohti , Hu Sishun , Grantham Ayslinn , Yu Qigui 
Published: January 2023

Abstract
The poxviruses including vaccinia virus (VV) and canarypox virus (ALVAC) have shown a strong preference for binding and infection of human cells from the monocytic lineage, particularly primary human monocytes (PHMs). In this study, we investigated whether specific molecules on the surface of PHMs regulate the preferential binding and infection of VV and ALVAC to this cell population. We found that the cleavage of glycosylphosphatidylinositol-anchored proteins (GPI-APs) on primary human monocytes by phosphatidylinositol-specific phospholipase C (PI-PLC) and the blockage of GPI-APs with mouse sera raised against GPI-APs significantly reduced the binding of VV and ALVAC to the cell surface, and subsequently inhibited viral infection. This reduction is not related to abatement of phagocytosis as internalization of latex beads by PHMs was not affected by PI-PLC digestion. As well, the human monocytic cell lines THP-1, U937 and U1 express high, moderate and low levels of surface GPI-APs, respectively. The susceptibility of these cells to VV and ALVAC infection correlated to levels of surface expression of GPI-APs. In addition, THP-1 cells showed reduced susceptibility to VV and ALVAC infection when they were mutated by ethyl methanesulfonate (EMS) or aerolysin (AE) to express low or undetectable surface GPI-APs. Thus, specific GPI-APs on the surface of monocytes are involved in poxvirus binding and infection, and may act as monocyte-specific surface receptors for poxviruses.