bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical function of myeloid SOCS3 is in limiting the neuroinflammation of EAE (147.21)
Authors: Qin Hongwei , Yeh Wen-I , De Sarno Patrizia , Muldowney Michelle , Reynolds Stephanie , Holdbrooks Andrew , Yanagisawa Lora , Harrington Laurie , Raman Chander , Benveniste Etty 
Published: January 2023

Abstract
Macrophages and microglia are central players in the pathogenesis of inflammatory diseases in the CNS, such as Multiple Sclerosis. SOCS proteins are critical feedback inhibitors of the JAK/STAT pathway, and negatively regulate innate and adaptive immune responses. Our Previous Studies indicated that SOCS3 is a negative regulator of macrophage and microglia activation. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is used to study the function of SOCS3 in neuroinflammation. Mice with conditional SOCS3 deletion in myeloid lineage cells (LysMCreSOCS3fl/fl) were generated from SOCS3fl/fl mice. Our results indicated that LysMCreSOCS3fl/fl mice are remarkably vulnerable to MOG-induced EAE, with features characteristic of atypical EAE, an earlier onset and more severe of EAE than SOCS3fl/fl mice. The lack of SOCS3 in myeloid lineage cells led to enhanced infiltration of inflammatory cells and enhanced demyelination in the cerebellum, and expression of inflammatory cytokines and chemokines in the cerebellum, and an immune response dominated by Th1 cells. Furthermore, the adoptive transfer experiments demonstrated that macrophage with SOCS3 expression rescues LysMCreSOCS3fl/fl mice from atypical EAE by inhibition of IFN-γ, IL-6, CCL2 and CXCL10 expression. Our study suggests that SOCS3 is a critical negative regulator in EAE pathogenesis, specifically in the development of atypical EAE. SOCS3 may service as an approach to new therapeutics for MS patients.
Characterization of mast cell-dendritic cell interactions (147.27)
Authors: Carroll-Portillo Amanda , Kawakami Yuko , Kawakami Toshi , Cambi Alessandra , Lidke Diane 
Published: January 2023

Abstract
Mast cells (MCs), while central to allergy, are recently recognized as functioning in a broader immune context. In addition to mediating dendritic cell (DC) responses through secreted products, MCs also present antigen directly to T-cells. While the ability of MCs to present antigen under certain conditions is clear, their in vivo role in relation to other immune cells is still under investigation. Upon activation of MCs, a variety of soluble factors are secreted to which DCs respond including TNFα, prostaglandins, and histamine. Additionally, both MCs and DCs localize within many of the same tissues, and, as we demonstrate, reside in close proximity. Thus, it is possible that MCs and DCs could work in conjunction to mediate immune responses through both indirect and direct mechanisms. To characterize MC-DC interactions, we use a combination of ELISAs, flow cytometry, immunohistochemistry, and live cell confocal microscopy. We show that MCs and DCs form prolonged interactions in the presence of multivalent antigen responsible for crosslinking IgE-primed FcϵRI and activating MCs. These direct interactions result in material transfer from MCs to DCs without inducing DC maturation. Both the exchange of soluble mediators and cell-cell contact resulted in the production of anti-inflammatory cytokines. Interestingly, direct contact appears to induce a stronger albeit delayed response.
Signaling via neurokinin-1 receptor abrogates CREB translocation and of IL-10 secretion in myeloid dendritic cells resulting in potent Th1 and Tc1 biasing function (147.6)
Authors: Larregina Adriana , Janelsins Brian , Sumpter Tina , Mathers Alicia , Tkacheva Olga , Morelli Adrian 
Published: January 2023

Abstract
Neuropeptides regulate innate and adaptive immunity and immune cells express neuropeptide receptors like the pro-inflammatory neurokinin-1 receptor (NK1R). NK1R agonists favor cellular immunity. Myeloid dendritic cells (DC) that link innate and adaptive immunity, express functional NK1R. Yet the ability of NK1R agonists to direct DC functions is unknown. We analyzed the effects of signaling mouse bone marrow derived DC via NK1R (NK1RDC) on their abilities to stimulate Ag-specific T-cell responses. Untreated DC secreted IL-10 constitutively and IL-10 transcripts and protein secretion was inhibited in NK1RDC. Abrogation of IL-10 correlated with a significant decrease of pCREB in DC nuclei and DC maturation without IL-12p70 secretion. Transfer of NK1RDC to C57BL/6 (B6) mice induced Ag-specific CD4+Th1 and CD8+Tc1 immunity that was inhibited by restoring IL-10 secretion in the adoptively transferred DC. As Th1 and Tc1 responses required IL12p70, we studied the source of IL-12p70 by comparing the immune response elicited by NK1RDC injected to B6WT,IL-12p35-/- or CD11c+DTR mice (depleted of endogenous DC). In these conditions type-1 immunity required lacking of IL-10 by transferred DC and IL-12p70 secretion by lymphoid organ DC. We conclude that NK1R signaling of Ag-bearing DC promote potent type-1 immunity mediated by inflammatory myeloid DC that regulate the T-stimulatory functions of lymphoid organ resident DC.
Diet-induced obesity enhances T cell activation by splenic dendritic cells (147.9)
Authors: Granados Valerie , Ramirez Oscar , Garza Kristine 
Published: January 2023

Abstract
In the U.S., over two-thirds of adults are overweight or obese, which correlates with chronic inflammation and is marked by an inability to effectively clear infection. Leptin, a pleiotropic adipokine, directly affects immunity via actions on immune cells. In vitro studies demonstrate that acute exposure of DC to leptin enhances DC function. Our recent in vivo data however, demonstrates that DC function is enhanced in the absence of leptin suggesting that leptin negatively regulates DC. The current study re-evaluates the effect of leptin on immunity using a diet-induced model of obesity (DIO). Weanling C57Bl/6 male mice were fed a high fat or lean diet for 12 weeks. At 28 weeks, when weight gain significantly correlated with serum leptin concentrations, splenic DC (sDC) were harvested and assessed for phagocytosis and antigen processing. Both functional assays showed no difference between DIO and lean mice. sDC were also assessed for activation of antigen-specific T cells, which was measured as a function of interferon gamma production. Data demonstrate that DIO sDC were more immunogenic than lean sDC and that T cell activation positively correlated with interleukin-12 production by the sDC during co-culture. Together, the data show that DIO enhances sDC ability to activate T cells ex vivo suggesting that high circulating levels of leptin increase sDC function. We therefore surmise that deregulated immunity in obese patients may be the result of overactive DC.
Aire expression in human lymph nodes: a comparison of type I diabetics and healthy controls. (148.14)
Authors: McMahon Eileen , Metzger Todd , Anderson Mark 
Published: January 2023

Abstract
Autoimmune regulator (Aire) was identified in 1997 as the gene mutated in autoimmune polyendocrine syndrome type I (APS-1), a disease in which patients develop a wide range of autoimmune diseases including thyroiditis and type I diabetes (T1D). Aire is known to be highly expressed in medullary thymic epithelial cells where it upregulates tissue-specific antigens for negative selection. Recently, using transgenic reporter mice, our lab has characterized a rare population of cells in secondary lymphoid organs that also expresses Aire. These eTACs (extra-thymic Aire-expressing cells) displayed a “tolerizing” cell surface phenotype (MHC class IIhi, CD80-, CD86-) and promoted tolerance to prevent autoimmune diabetes. The goal of this study was to identify and characterize eTACs in human lymph node (LN) and to compare eTACs in T1D and healthy controls. Immuno-fluorescence revealed Aire-expressing cells in both pancreatic and non-pancreatic LN. Aire+ cells were relatively rare but showed the typical “nuclear speckling” pattern for staining. Co-staining was performed to examine both their cell linage and antigen presentation capabilities. Quantitative PCR was used to confirm the LN Aire expression. Finally, similar methods were used to compare the Aire expression in pancreatic LN of T1D and healthy controls. Overall, our data reinforces the fact that Aire is indeed expressed outside the thymus and that it may potentially have a role in peripheral tolerance in humans.
T cell specific overexpression of Bcl-3 impairs T cell activation and causes severe colonic inflammation (148.17)
Authors: Masri Joumana , Wörns Marcus , Reissig Sonja , Hövelmeyer Nadine , Waisman Ari 
Published: January 2023

Abstract
Bcl-3 is a proto-oncogene belonging to the IκB family. It has been reported to exert both inhibitory as well as activating function, depending on the cellular context. It has previously been shown that its overexpression slows T cell activation very early in T cell responses to antigen. We could show by endoscopy and immunohistochemistry that mice overexpressing Bcl-3 in T cells (CD4-Cre ROSA-CAGs-STOP-Bcl-3-EGFP, henceforth termed CD4-Cre Bcl-3) develop spontaneous colitis and could observe a massive infiltration of immune cells into the colonic mucosa. CD4+ T cells overexpressing Bcl-3 show enhanced survival capacity in in vitro culture, but have an impaired proliferative capacity when stimulated in vitro or when adoptively transferred into lymphopenic Rag1-/- recipients. When compared to control littermates CD4-Cre Bcl-3 mice have less peripheral memory/effector T cells and less Th1 cells, whereas Th17 numbers remain unaltered. Naïve T cells overexpressing Bcl-3 show defects in in vitro differentiation to the Th1 or Th17 fate. Ex vivo isolated Bcl-3-overexpressing regulatory T cells display diminished suppressive capacity in vitro and in vivo. Interpretation of the observed phenotype will require the elucidation of the molecular role of Bcl-3 in T cell activation and proliferation.
Interleukin-7 receptor alpha contributes to experimental autoimmune encephalomyelitis (148.24)
Authors: Jopek Ashbaugh Jessica , Brambilla Roberta , Malek Thomas , Bethea John 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a neurodegenerative disease characterized by extensive inflammation, demyelination, and axonal damage. The interleukin-7 receptor alpha (IL7Rα) chain is an essential subunit for the signaling receptors of both interleukin-7 (IL7) and thymic stromal lymphopoietin (TSLP), which are involved in lymphocyte development, function, and homeostasis. Recently a mutation in the IL7Rα chain locus has been identified as a risk factor for MS. We show that mice with IL7Rα expression limited to thymic tissue (IL7RTgIL7R-/-) display a less severe form of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. However, TSLPR-/- mice showed no protection from disease. Furthermore, anti-IL7Rα treatment in wild type (WT) mice after disease onset significantly decreased EAE severity and lymphocyte infiltration into the CNS, which was accompanied by a relative increase in resident microglia. Additionally, Rag-/- chimeric mice grafted with IL7RTgIL7R-/- or WT bone marrow cells displayed equivalent disease severity, implying that IL7Rα on a non-hematopoietic cell population contributes to EAE. Taken together, our data shows that systemic blockade of IL7Rα reduces EAE severity, and therefore serves as an optimal target for MS therapies.
Indoleamine 2,3-dioxygenase: from catalyst to signaling function (148.4)
Authors: Fallarino Francesca , Pallotta Maria Teresa , Orabona Ciriana , Volpi Claudia , Vacca Carmine , Belladonna Maria Laura , Bianchi Roberta , Fioretti Maria Cristina , Puccetti Paolo , Grohmann Ursula 
Published: January 2023

Abstract
Tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile regulator of immunity. IDO catalytic activity is pivotal in innate/inflammatory responses. In inflammation, interferon γ (IFN-γ) is the primary IDO inducer to prevent hyperinflammatory responses, yet the enzyme is also responsible for long-term self tolerance effects. Here we show that treatment of mouse DCs with transforming growth factor β (TGF-β), or with high dose of CpG-ODNs conferred regulatory effects on IDO that depended not only on its enzymatic activity. A moonligthing function of IDO was revealed involving intracellular signaling events responsible for long-term maintenance of its own expression. Our recent data revealed that autocrine/paracrine TGF-β can induce IDO- long-term regulatory functions, with a primary role in the generation and maintenance of regulatory T (Treg) cells. Thus, depending on a specific physiopatological context, IDO and pDCs will exhibit adaptable and integrated modes of immune control.Thus IDO can meet different environmental needs, turning its own expression from an IFN-γ-dependent, intense but short course (e.g., innate/inflammatory responses) to a TGF-β-driven, tonic and prolonged form of activation (as required by tolerance mechanisms).
IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis (148.6)
Authors: Park Mi-kyung , Oh Hye-Jwa , Heo Yang-Mi , Park Eun-Mi , Park Sung-Hwan , Cho Mi-La 
Published: January 2023

Abstract
IL-15 is a pleiotropic proinflammatory cytokine that appears to help mediate the pathological bone loss. This study was undertaken to explore the signaling molecules essential for osteoclastogenesis mediated by IL-15 in rheumatoid synovial fibroblasts. The levels of RANKL and PLD1 but not PLD2 were upregulated significantly by IL-15, and the RANKL level was significantly upregulated by PA in rheumatoid synovial fibroblasts. Blocking PA production with 1-butanol and siRNA against PLD1 significantly inhibited the IL-15-stimulated expression of RANKL and PLD1. IL-15 levels were significantly higher in serum and synovial fluid from patients with RA than in osteoarthritis patients and healthy controls. IL-15 and PA induced osteoclast formation through the MAPKs and NF-kB signaling pathways. Conclusion. Activation of PLD1 contributes to IL-15-mediated osteoclastogenesis via the MAPKs and NF-kB signaling pathways in rheumatoid synovial fibroblasts. Our data suggest that PLD1 might be an efficient therapeutic strategy for preventing bone destruction in rheumatoid arthritis
The role of TCR affinity in thymic regulatory T cell development (148.9)
Authors: Lee Hyang Mi , Hsieh Chyi-Song 
Published: January 2023

Abstract
TCR-dependent generation of natural Foxp3+ CD4+ regulatory T cells (Treg) in the thymus is essential for maintaining self-tolerance. Although a simply affinity model of self-antigen recognition is widely accepted as governing thymic Treg development, it is poorly substantiated experimentally. To address the mechanism by which TCR interactions with peptide:MHC complex result in Treg development, we are analyzing the ability of a variety of TCRs to facilitate Treg development due to interactions with OVA(323-339) expressed via the RIP-mOVA transgene. To obtain TCRs with varying reactivity to OVA, we sequenced TCR-alpha chains of proliferating CD4+ T cells from DO11 TCR-beta transgenic mice stimulated in vitro with OVA peptide. OVA reactivity was confirmed by retroviral transduction of individual TCRs into a hybridoma cell line expressing an NFAT-GFP reporter for TCR activation. Approximately 9 TCRs have thus far been obtained that show up to 1000-fold differences in sensitivity to OVA in vitro. Sensitivity to OVA appeared to correlate with the ability to facilitate RIP-mOVA dependent Treg development. Using DO11-alpha-beta TCR as a reference point for TCR-cognate peptide interaction, one TCR with a 1,000 fold lower reactivity to OVA was unable to facilitate Treg development, whereas TCRs within 100-fold sensitivity were capable. Thus, these preliminary data allow us to begin to quantify the nature of TCR interactions with peptide:MHC required for Treg selection.
CXCL13 and CXCR5 expression by Non-Small Cell Lung Carcinoma (149.15)
Authors: Singh Rajesh , Singh Shailesh , Grizzle William , Lillard Jr. James 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Chemokines and their corresponding receptor have been shown to play important role in tumor progression, including lung cancer. In this regard, we have previously shown that the chemokine receptor CXCR5 is involved in metastatic dissemination in breast and prostate cancers. In this study we show CXCR5 is highly expressed by lung cancer cell lines and non-small cell lung carcinomas (NSCLC) tissues, than compared to non-neoplastic lung tissue. CXCL13, which is the only natural ligand for CXCR5, is also expressed within the lung tumors. Retrospective analysis of CXCR5 expression in 45 patients specimens showed significantly higher expression of CXCR5 in squamous cell carcinoma and adenocarcinoma samples. Interestingly, the nuclei of advanced tumor cells from these tissues were also positive for CXCR5 in more than 50% of these cases. Furthermore, ELISA showed significantly higher serum levels of CXCL13 by serum of patients with either adenocarcinoma or squamous cell carcinoma (n = 31), than compared to normal controls (n = 9). The mechanism underlying these clinically and biologically important findings need to be further explored.
Critical role for IL-13Rα1 in Th2 cell homing (149.2)
Authors: Lu Wen , Yang Tianshu , Liu Xiaoling , Kheradmand Farrah , Corry David 
Published: January 2023

Abstract
Interleukin 13 receptor alpha1 (IL-13Rα1) binds to IL-13 and is required for IL-13 signaling. Although clearly expressed on non-immune cells, the presence and function of IL-13Rα1 on T cells is still controversial. Our laboratory generated IL-13Rα1-/- mice and studied the role of IL-13Rα1 in T cell function and allergic lung disease. As expected from prior studies, compared with identically treated wild type control mice, IL-13Rα1-/- mice challenged with the spores of Aspergillus niger failed to acquire an asthma-like phenotype, most likely due to the lack of IL-13 signaling in the lung. Surprisingly, we further discovered significantly fewer T helper type 2 (Th2) cells in the lung in IL-13Rα1-/- mice after spore challenge, suggesting that IL-13Rα1 may have a direct role in regulating Th2 cell function. To understand this phenomenon further, we used qRT-PCR to define the expression of IL-13Rα1 on distinct T helper effector subsets, finding IL-13Rα1 mRNA only expressed in differentiated Th2 cells. Further studies revealed that Th2 cell-intrinsic IL-13Rα1 is dispensable for Th2 cell linage commitment, but is required for Th2 cell homing to the lung using an adoptive T cell transfer system. Thus, although further studies are required, our findings suggest that IL-13Rα1 is selectively upregulated in Th2 cells and mediates Th2 cell homing to lung in allergic lung disease. These findings potentially reveal a novel mechanism by which IL-13 regulates allergic responses.
Studying the mechanisms for increased IL-7Rαlow Memory CD8+T cells in the elderly (150.11)
Authors: Shin Min Sun , Lee WonWoo , Lee JinSoo , Kim SangHyun , Lee NaEun , Kang InSoo 
Published: January 2023

Abstract
We recently reported an age-associated expansion of IL-7Rαlow memory CD8+T cells that have limited T cell receptor (TCR) repertoire and impaired TCR-mediated proliferation. Here we found that in the elderly, cytomegalovirus (CMV)-infected donors had a higher frequency of IL-7Rαlow memory CD8+ T cells than CMV-uninfected donors, suggesting the role for CMV infection in expanding this cell subset. The frequency of IL-7Rαlow memory CD8+ T cells was higher in CMV-infected elderly donors than in CMV-infected young donors, indicating a potential role for CMV infection in the age-associated expansion of IL-7Rαlow memory CD8+T cells. Of interest, the frequency of IL-7Rαlow memory CD8+ T cells also was higher in CMV-uninfected elderly donors than in CMV- uninfected young donors, suggesting the role of a CMV-independent factor(s) for the expansion with aging. We found that IL-7Rαlow memory CD8+T cells from young donors showed better survival in response to IL-15, a cytokine known to promote proliferation and survival of memory CD8+ T cells. However, there was no significant difference in IL-15-mediated proliferation of IL-7Rαlow memory CD8+ T cells and IL-15 expression by monocytes between young and elderly people. Our results suggest that CMV-dependent and -independent mechanisms are involved in the expansion of IL-7Rαlow memory CD8+ T cells with aging and that IL-15 could be a CMV-independent factor.
Elevated functional Interleukin-15 provided by human peripheral immune cells in Multiple Sclerosis patients (150.8)
Authors: Mohebiany Alma , Schneider Raphael , Ifergan Igal , Beausiegle Diane , Duquette Pierre , Prat Alexandre , Arbour Nathalie 
Published: January 2023

Abstract
Activated CD8 T cells have been involved in several autoimmune diseases, including Multiple Sclerosis (MS); CD8 T cells from MS patients bear an enhanced activation profile compared to those from controls; but the role of cytokines in boosting CD8 T cell activation in MS is not elucidated. While elevated levels of IL-15, a key cytokine for memory CD8 T cells, has been reported in serum and on peripheral leukocytes in MS patients compared to controls, no study has addressed whether these increased levels influence CD8 T cell functions. The goal of our study is to assess surface IL-15 and IL-15Rα expression on human leukocytes and determine whether these expression levels are sufficient to enhance human CD8 T cell functions. An increased proportion of ex vivo B cells from MS patients express IL-15 compared to controls, and upon contact with CD40L, B cells obtained from controls increased IL-15 expression, reaching levels similar to those observed in MS patients. We use in vitro flow cytometry-based assays to show that effector functions (granzyme B) in CD8 T cells are significantly enhanced upon co-culture with IL-15-expressing B cells. IL-15 has a greater impact on CD8 T cells from MS patients than controls and we provide evidence that CD8 T cells pre-exposed to IL-15 are more cytotoxic than untreated CD8 T cells. We not only demonstrate that multiple leukocytes can modulate CD8 T cell responses by providing IL-15, but also support a role for B cells in MS pathogenesis.
TGF-β1 suppresses mast cell functions in vivo. (151.15)
Authors: Fernando Josephine , Ryan John 
Published: January 2023

Abstract
We have previously demonstrated the immunosuppressive effects of TGFβ1 on IgE signaling in human and mouse mast cells in vitro. Here we extend our focus to in vivo models, including mast cell-dependent airway inflammation. TGFβ1 injection into unimmunized mice reduced peritoneal mast cell numbers and their expression of the high affinity IgE receptor, as well as cKit. Further, TGFβ1 delivered as an aerosol to ovalbumin-immunized mice decreased pulmonary eosinophilic inflammation and mucus production. TGFβ1 did not affect Syk, Stat5, Fyn or Akt mRNA expression. However, mast cell Fyn and Stat5 protein levels were diminished by TGFβ1 treatment in vitro, while Akt and Syk were unaffected. Interestingly, we found that mast cells from the 129/SvJ mouse strain were resistant to TGFβ1-mediated suppression. Unlike their C57BL/6 counterparts, 129/SvJ mast cells did not demonstrate reduced IgE receptor expression or IgE-mediated cytokine production after culture with TGFβ1. These data show that TGFβ1 is a potent suppressor of the mast cell response that may be altered by host genetic makeup. We further find that the effects of TGFβ1 include selective reduction in key IgE-mediated signaling molecules.