bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of c-Ski and TGFβ signaling in autoimmunity
Authors: Ong SuFey , Hauri-Hohl Mathias , Ziegler Steven F 
Published: January 2023

Abstract
TGFβ is involved in both Treg and Th17 differentiation via its induction of Foxp3 and RORγt. The oncogene c-ski regulates TGFβ function by inhibiting SMAD2/3 from both binding to SMAD4 and to DNA, repressing the transcription of TGFβ-inducible genes. Previously, we have shown that the absence of ski in medullary thymic epithelial cells (mTECs) limits cellular growth due to unchecked TGFβ signaling. Given that central role of Treg and Th17 cells in the development of autoimmune disease, we explored the role of Ski and TGFβ signaling in T cell function and differentiation. We demonstrate that the absence of Ski in CD4+ T cells leads to amplified TGFβ sensitivity as shown by increased Th17 differentiation at low levels of TGFβ in vitro. Additionally, Foxp3CreSkifl/flT cells polarized in the presence of TGFβ and IL-2 in vitro lead to increased Treg conversion in culture, suggesting that Ski may also play a role in Treg stability. To determine the role of Ski in an autoimmune disease model in vivo, we transferred Ski-deficient or WT naïve CD4+ T cells into Rag1−/− host mice. Ski-deficient T cells induced significantly greater colitis disease severity that was mirrored by increases in double-producing IL-17A and IFNγ pathogenic CD4 T cells. In conclusion, we have shown that Ski functions as a modifier of TGFβ signaling in CD4+ T cells and can directly influence the outcome of autoimmune disease pathogenesis.
Modelling endothelial cells to investigate lymphocyte proliferation under inflammatory conditions
Authors: Kulkarni Aneesha , Westfall Jessica , Segal-Abramson Tzvia 
Published: January 2023

Abstract
Bordetella pertussis is a gram-negative bacteria and the causative agent for whooping cough, a toxin mediated respiratory disease, which causes extensive damage to epithelium in the trachea and bronchial mucosa.
In the absence of a human model to study vascular leukocyte recruitment to the respiratory system, and tissue injury repair, we propose an in vitro model of endothelial cells (ECs) derived from embryonic stem cells (ESCs). We hypothesize that this model may be used to study the proliferation of Th17 and Treg cells during respiratory infection induced with B. pertussis antigens. Previous studies have shown that ECs constitutively express MHC II molecules allowing antigen presentation to recipient CD4+ T cells leading to a pro-inflammatory response. In addition, it has been demonstrated that human allogeneic EC induce Treg and Th17 proliferation.
In this study, we differentiated mouse ESCs in vitro to endothelial cells in the presence of VEGF and bFGF. The cells were enriched for endothelial cell surface adhesion markers CD31 and CD144. Using flow cytometry, qPCR and immunofluorescence, we confirmed the expression of endothelial markers vWF and CD144 with 8% of our population double-positive for CD31 and CD144.
The current model will be used to study pro-inflammatory response and T cell polarization will be assessed by activating endothelial cells with B. pertussis antigens or IFN-γ and then co-culturing with CFSE stained CD4+ T cells in polarizing conditions for 4 days.
We anticipate that this study will contribute important information about endothelial regulatory response to injury and inflammation during whooping cough.
Activation and infiltration of neutrophils in the cerebellum and brainstem is associated with the atypical experimental autoimmune encephalomyelitis phenotype
Authors: Yan Zhaoqi , Liu Yudong , Gibson Sara A. , Lee Kevin , Benveniste Etty N. , Qin Hongwei 
Published: January 2023

Abstract
The JAK/STAT signaling is critical for the initiation, regulation and termination of immune responses, and dysregulation of JAK/STAT signaling is associated with many pathological conditions such as multiple sclerosis. We previously demonstrated that myeloid lineage–specific deletion of SOCS3, a negative regulator of STAT3, resulted in a severe, non-resolving atypical form of experimental autoimmune encephalomyelitis (EAE). Mice with atypical EAE exhibit ataxia and tremors and are characterized by lesions, inflammatory infiltrates, elevated STAT3 activation, and increased cytokine and chemokine expression in the cerebellum. In the current study, our data indicate that the atypical EAE observed in LysMCre-SOCS3fl/fl mice is associated with elevated pro-inflammatory cytokines and chemokines in the cerebellum and brainstem. Greater numbers of infiltrating neutrophils were found in the cerebellum and brainstem of LysMCre-SOCS3fl/fl mice compared to SOCS3fl/fl mice, however, neutrophil numbers in the periphery were comparable. Infiltrating neutrophils in LysMCre-SOCS3fl/fl mice have hyper-activated STAT3 and express higher levels of IL-6 and CCL2. Recruitment of Ly6Chi monocytes in LysMCre-SOCS3fl/flmice is comparable to SOCS3fl/fl mice. During the peak stage of disease, LysMCre-SOCS3fl/fl mice had increased numbers of both Th1 and Th17 cells, and significantly increased numbers of IFN-γ+IL-17+ T cells in the cerebellum and brainstem, compared to SOCS3fl/fl mice. Depletion of neutrophils in LysMCre-SOCS3fl/fl mice prevented the atypical EAE phenotype, rather, classical EAE was observed. This study illustrates the critical function of neutrophils in the pathogenesis of atypical EAE.
Persistence of inflammatory adipose tissue immune cells despite weight loss in obese mice
Authors: Zamarron Brian F , Mergian Taleen , Martinez-Santibanez Gabriel , Luan Danny , Lumeng Carey N 
Published: January 2023

Abstract
Obesity causes dramatic changes to the adipose tissue immune environment including the recruitment and activation of macrophages. The inflammatory polarization of these cells is thought to play a critical role in the severity of insulin resistance associated with obesity. Weight loss can improve insulin resistance, but little is known concerning the effects of weight loss on immune activity in adipose. Diet switch from a 60% high-fat diet to 13% normal-fat diet was used to induce weight loss in diet-induced obese C57Bl/6 mice. Adipose tissue structural changes were evaluated by histology. Leukocyte populations were analyzed by flow cytometry, including sorting and comparing cytokine expression of adipose tissue macrophages before and after weight loss. Weight loss improved glucose tolerance and reduced serum insulin. However, extensive adipose fibrosis developed during weight loss and was associated with macrophage accumulation. Analysis of adipose macrophages after weight loss showed they retained an inflammatory gene expression profile similar to those found during obesity. These macrophages were derived primarily from older cells present during obesity. These macrophages were maintained though high proliferation and low apoptosis. The data indicate that inflammatory activation of adipose macrophages is not sufficient for whole body metabolic dysfunction, but the retained macrophages may promote adipose tissue fibrosis while impacting adipocyte health and function.
Serum amyloid A induces T lymphocyte migration through chemokine receptor CXCR3
Authors: Thompson Aaron J. , Omer Linda , He Rong Lucy 
Published: January 2023

Abstract
Serum amyloid A (SAA) is a major acute-phase protein with cytokine/chemokine-like properties. It can be expressed at sites of inflammation and induce the migration of immune cells including T lymphocytes to the inflammatory sites. SAA plasma concentration can be 1000 times higher in patients with autoimmune diseases such rheumatoid arthritis, than in healthy people. However, its precise role in inflammation and infection remains unclear. SAA is known to bind to several receptors such as FPRL1, TLR2, and TLR4, etc. It is possible that SAA also use other chemokine receptors to recruit immune cells during the inflammation. In our previous study, we used a mathematical approach called Natural Vector Method (NVM) to analyze the genetic information of all major human chemokines and SAA and found that chemokine receptor CXCR3 may be a new receptor for SAA. We reported here that SAA indeed can induce MAP kinase ERK activation in the CXCR3 over-expressed cell line, and trigger the receptor-mediated intracellular calcium mobilization. Our chemotaxis experiments also showed that SAA promotes CXCR3-overexpressed cell migration. These findings indicate that SAA may use lymphocyte chemokine receptor CXCR3 to recruit activated lymphocytes to the inflammation sites. We will further investigate the signaling pathways involved in the CXCR3 mediated SAA-induced cell migration. We hope that our research work not only helps to understand the function of SAA, but also introduces a new way of finding receptors for the endogenous molecules. [This study is supported by NSF grant DMS-1119612 and NIH grant 1SC3GM098180 awarded to Rong L He]
IL-7 receptor pathway in Xenopus laevis
Authors: Coyne William E , Foulkrod Ashley M , Lambert Lisa A , Appasamy Pierette M 
Published: January 2023

Abstract
IL7/IL7 receptor signaling is essential for development of mammalian B and T cells, in particular γδ T cells. The IL7 receptor is a heterodimer comprised of the IL7R α chain and the γ common chain that is shared by other IL2 family cytokines that signal through the JAK-STAT pathway. Since the SCID-like phenotype observed in IL7-knockout mice is less severe than that seen in IL7R knockout mice, there may be other cytokines that signal through the IL7R. In fact, thymic stromal lymphopoietin (TSLP) can substitute for IL7 and signal through the IL7R, at least in mice and humans. We have begun to address the role of IL7/IL7R signaling in Xenopus laevis, in which γδ T cells are abundant, particularly at the larval stages. Although an IL7R α ortholog is present in frogs, BLAST searches of the Xenopus tropicalis genome and gene synteny analyses strongly suggest the absence of IL7. To better understand the function of the IL7 heterodimer receptor in frogs, we have created protein models of both IL7R and the γ common chain (γc). We identified regions of the predicted X. tropicalis IL-7R cDNA that are well-conserved among lower organisms and created primers for use in PCR analyses of cDNA products from oligo-dT primed RNA isolated from the Xenopus laevis thymus. Analysis of the PCR products is currently underway.
IL-6 induces IL-21 and B cell helper function in CD8 cells
Authors: Yang Rui , Rincon Mercedes 
Published: January 2023

Abstract
Interleukin 6 (IL-6) is a pro-inflammatory produced by various cell types in response to external stimuli including trauma, stress and infection. IL-6 signaling plays an important role in immune reaction and progression of several autoimmune diseases by programing CD4 cell differentiation and effector functions. CD8 cells was first believed to primarily function as cytotoxic effector cells, their helper cell effector function has been better understood till recently. During activation, CD8 cells can be primed in different cytokine environments to differentiate into different CD8 effector subtypes, including Tc1, Tc2 and recently identified Tc17. Although the role of IL-6 in CD4 cell differentiation and effector function is well known, how IL-6 may regulate CD8 cell differentiation is less studied. In this study, we show that IL-6 induces IL-21 production in CD8 cells during activation through the transcription factor Stat3. Importantly, IL-6 also differentiates CD8 cells to an effector subset producing high IL-21 but low IFN-γ and IL-2. IL-6R expression level in CD8 cells determines the subset of cells that capable of making IL-21. Similar to IL-21 producing CD4 cells, surprisingly, IL-21 producing CD8 cells provides B cell help by inducing isotype switching and promoting antibody production in vitro and in vivo during influenza A flu infection. Thus, our study suggests that IL-6 could differentiate CD8 cells into IL-21 producing B cell helper subset that may play a unique role in restricting infection and the progression of autoimmune diseases.
Notch signaling directs splenic resident hematopoietic stem cell fate decisions
Authors: Vanderbeck Ashley Nicole , Land Ruben H. , Mumau Melanie D. , Lynch Elizabeth D. , Golec Sophia B. , Punt Jennifer A. , Emerson Stephen G. 
Published: January 2023

Abstract
Adult hematopoiesis occurs primarily in the bone marrow (BM), generating mature blood cells as well as maintaining a heterogeneous pool of self-renewing hematopoietic stem cells (HSCs). However, studies suggest that the BM may not be the only site of adult hematopoiesis: during times of BM hematopoietic distress stemming from radiation or disease, the spleen can independently reconstitute the blood. Given that the spleen does indeed contain a small, resident population of lineage-sca1+ckit+CD48-CD150+ long-term (LT)-HSCs with potent reconstitution ability, we investigated the peripheral blood cell contribution of these extra-medullary HSCs by transplanting UBC-GFP Tg reporter splenic fragments into a splenectomized syngenic wildtype mouse and tracking the blood cell production over time. While the spleen gives rise to both mature myeloid and lymphoid cells, we find that the proportion is skewed in favor of T cells. We see spleen-derived donor HSCs generating CD4+CD8+ double positive thymocytes for over five months post-transplant, suggesting that this peripheral T cell population derives from a long-lived stem or progenitor cell resident in the spleen. RNA sequencing demonstrates that splenic LT-HSCs are more responsive to Notch signaling than BM LT-HSCS, as indicated by increased levels of Hes1 transcription and decreased levels of the granulocyte/monocyte (GM) lineage priming genes Mpo, Gfi1, and Fcgr2b. Taken together with our finding that splenic HSCs have higher levels of cytoplasmic Notch2, we suggest that the Notch2-Hes1 axis is simultaneously repressing GM priming and enforcing T cell programming even among the most immature HSCs resident in the spleen.
Irritant contact dermatitis is regulated by antioxidative enzyme NAD(P)H:quinone oxidoreductase (Nqo1).
Authors: Kitajima Masayuki , Kimura Akihiro , Suzuki Harumi 
Published: January 2023

Abstract
Irritant contact dermatitis (ICD) is the most common occupational skin inflammatory disorder caused by the exposure of chemical or physical irritants. Local release of inflammatory mediators such as cytokines, lipid mediators, and reactive oxygen species (ROS) are known to be important in the establishment of ICD. Antioxidative enzymes such as Nqo1 are known to be responsible for the degradation of ROS. Therefore, in the current study, we focused on the involvement of Nqo1 in ICD.
In the mouse ICD model using croton oil, we found that Nqo1-deficient mice exhibited increased ear swelling and augmented expression of proinflammatory cytokines such as IL-6 and IL-17A in the skin. As we expected, it is indicated that Nqo1 has protective role against ICD. However, it is not applicable for general inflammatory responses, because the knockout mice showed unaltered response in the allergic contact dermatitis mouse model. Interestingly, we found that severe reduction of Vγ5Vδ1+ dendritic epidermal T cells (DETCs) in the skin of Nqo1 deficient mice, which are reported to inhibit ICD. Transfer of DETCs into RAG−/− mice revealed impaired survival of Nqo1-deficient DETCs. In addition, Nqo1-deficient DETCs were sensitive to oxidative stress-induced cell death, and anti-oxidant NAC treatment rescued decreased DETCs in Nqo1-deficient mice. These results suggest that Nqo1 regulates ICD through DETC development and/or homeostasis, possibly by antioxidative function.
Disruption of the gut microbiota by antibiotics exposure during early life promotes spontaneous Th2 responses and loss of tolerance to dietary antigens
Authors: Gustafsson Jenny K , McDonald Keely , Newberry Rodney 
Published: January 2023

Abstract
Allergic disorders, manifest by T helper 2 (Th2) type immune responses to environmental antigens, are rapidly increasing in children. Regulatory T cells (Tregs) limit Th2 responses, and Treg deficiencies are seen in children with allergic disorders, implying that Treg deficiencies or dysfunction underlie the pathogenesis of Th2 mediated disease. What incurs Treg deficiency and its relationship to the increasing incidence of allergy is unknown, however, studies have shown that the intestinal microbiota plays an important role in regulating Treg differentiation during early life. With this in mind we explored whether oral exposure to specific antibiotics in early life altered Treg populations and predisposed to Th2 responses. We found that exposure of mice to a combination of broad spectrum oral antibiotics between days 10 and 20 of life abrogated tolerance to a dietary antigen, ovalbumin (Ova). Exposure of mice to single antibiotics of varying spectra between days 10 and 20 of life had a range of effects from abrogation of oral tolerance to the spontaneous development of Th2 responses manifested by increased levels of IL-13 in the serum in the absence of challenge. Ongoing studies are evaluating the effect of the respective antibiotic regimens on the intestinal microbial community using 16S bacterial DNA sequencing, with the aim to link alterations in the microbial composition to the immunological profile of the respective treatment groups. In summary, our results show that disruption of the intestinal microbiota by exposure to specific antibiotics during a period in early life results in loss of Tregs, promotes Th2 immunity, and impair establishment of oral tolerance to dietary antigen.
The role of type 2 innate lymphoid cells in RSV-induced asthma exacerbation.
Authors: Warren Kristi J , Pavlik Jacqueline A. , DeVasure Jane M. , Dickinson John D. , Sisson Joseph H. , Wyatt Todd A. 
Published: January 2023

Abstract
Respiratory viral infections cause devastating airway inflammation and remodeling in asthmatic children and adults. Type 2 innate lymphoid cells (ILC2) have been characterized individually in both asthma and viral infections. We hypothesize that ILC2 are activated by IL-33 in our model, and thereby enhance the asthmatic phenotype in the lung. Asthma induction was performed in eight week old, female BALB/c mice using ovalbumin (OVA) sensitization and airway challenge. After the last airway challenge, mice were infected with RSV (3,250 TCID50 U/mouse). Lungs were collected for ILC2 sorting, immune cell quantitation, and analysis of IL-4, IL-13, IL-33 and IL-25 on days 1–4 of infection. A subset of lungs were collected and fixed for histological analysis. Results show that mucus production (PAS+ cells) and lymphocytic recruitment were enhanced with RSV infection and asthma. The expression of MUC5AC, CLCA3, IL-25 and IL-33 mRNA levels were increased at least two-fold in the lungs of OVA+RSV mice compared to RSV-infected alone. We detected comparable numbers of ILC2 in BAL fluid from both OVA+ and OVA+RSV mice, yet an evaluation of total lung lymphocytes yielded more ILC2 in the OVA+RSV mice as compared to OVA alone. ILC2 from OVA+RSV mice were sorted and treated with IL-33 for 24 hours. These cells produced greater IL-4 mRNA than cells isolated from OVA only mice. Our results describe a potential role for ILC2 in the exacerbation of asthma with RSV infection. Future studies are planned to determine the exact contribution of ILC2 to type 2 immunity and pulmonary function in our asthma-viral infection model.
Dual Blockade of OX40 and CD30 Signaling Reduces Memory Th2-driven Lung Inflammatory Responses to House Dust Mite Allergen
Authors: Gracias Donald Tom , Mehta Amit Kumar , Yagita Hideo , Croft Michael 
Published: January 2023

Abstract
Allergic asthma is an inflammatory disease that is induced by immune responses to airborne allergens in the lungs. Several studies have identified T cells as being important players in asthma, with Type 2 helper T cells (Th2) being a critical subset. The selective removal of pre-existing pathogenic memory Th2 cells could be a key process leading to enhanced tolerance. We have attempted to identify signaling molecules in the TNF superfamily that regulate memory Th2 cells in a house dust mite (HDM) model of allergic lung inflammation. C57BL/6J mice up-regulated OX40L to higher levels than other TNF family members measured in the lungs in response to HDM exposure. We then tested whether OX40-OX40L interactions were required for memory Th2 cell responses driven by HDM. While OX40-deficient mice displayed strongly reduced overall lung inflammation and Th2 development when challenged with HDM, therapeutic blocking of OX40L at the time of memory T cell reactivation did not result in similar inhibition of allergic responses, implying OX40L may have been important for initiation but not the memory response. Similar negative results were gained by targeting another TNF superfamily protein, CD30L, that was also up-regulated by HDM exposure. However, we observed significant reduction in airway inflammation when OX40L was simultaneously neutralized with CD30L. Dual blockade was found to target memory Th2 cell expansion and effector function but did not prevent accumulation of pTreg cells. This suggests that persisting memory responses to complex allergens are controlled by several co-stimulatory interactions, and only abrogation of signaling through multiple TNF superfamily members might promote airway tolerance.
Inducible Bronchus-Associated Lymphoid Tissue (iBALT) attenuates pulmonary Th2 responses
Authors: Hwang Ji Young , Southworth Kristen , Rangel-Moreno Javier , de la Luz Garcia-Hernandez Maria , Carragher Damian M , Randall Troy D 
Published: January 2023

Abstract
Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid tissue formed in the lung after pulmonary infection or inflammation. This local lymphoid tissue is structurally similar to conventional secondary lymphoid organs (SLOs), with separated B and T cell areas, specialized stromal cells and lymphoid dendritic cells (DCs). The presence of iBALT is typically associated with pulmonary pathology and advanced lung disease, particularly in patients with chronic obstructive pulmonary disease (COPD), rheumatoid lung disease, pulmonary fibrosis and chronic infections, suggesting that iBALT functions to exacerbate local immune responses and pathology. Here, we tested whether the presence of iBALT affected the pulmonary immune responses to allergens. We induced iBALT formation in neonatal mice by pulmonary administration of lipopolysaccharide (LPS), and when the mice were adults, sensitized and challenged them intranasally with ovalbumin (OVA). We found that mice with iBALT exhibited reduced Th2 responses, reduced eosinophil recruitment, reduced goblet cell hyperplasia and reduced mucus production. The presence of iBALT delayed the accumulation of Th2 cells and eosinophils in the lung following challenge and altered the spatial distribution of T cells in the lung. We also found that the more organized iBALT structure was, the fewer eosinophil infiltrates were observed in house dust mite (HDM)-induced allergic inflammation. Although Th2 cells are generated in mice with iBALT, they are concentrated in iBALT area and more dilute in lung parenchyma.
Overall, our studies expanded the field of iBALT from observation of what happens in pulmonary diseases to determining the machinery involved in the responses.