bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal epithelial cells regulate airway allergic inflammation through induction of IgA Abs and and IL-17A (175.9)
Authors: Bonnegarde-Bernard Astrid , Jee Junbae , Davis Ian , Boyaka Prosper 
Published: January 2023

Abstract
IKKβ-NF-κB signaling controls a large number of biological processes via tissue-specific regulation of inflammatory and anti-inflammatory responses. Using a model of oral antigen sensitization and mice with cell-specific deletion of IKKβ, we addressed the contribution of intestinal epithelial cells (IECs) to regulatory crosstalk between distant mucosal sites of the gastrointestinal tract and the airways. Mice with localized alteration of IKKβ-NF-κB signaling in IECs (IKKβΔIEC) exhibited unaltered IgE, but enhanced Th1-associated IgG2a Abs and IgA responses after oral antigen sensitization in the presence of cholera toxin. Interestingly, these mice showed reduced lung inflammation and mucus production after nasal allergen challenge. This protection required oral sensitization and was associated with the presence of IgA in bronchoalveolar fluids and increased IL-17A in the lungs. When orally sensitized with the same regimen, mice with a generalized IKKβ deficiency in cells of the myeloid lineage (IKKβΔMye) also were protected against nasal allergen challenge. Distinct mechanisms contributed to protection in IKKβΔIEC and IKKβΔMye mice since airway hyper-responsiveness and lung inflammation were completely abolished in IKKβΔMye mice, which also showed no IgA in bronchoalveolar fluid and lower IL-17A in the lung than IKKβΔIEC mice. In summary, IKKβ in IECs is sufficient for shaping immune responses to ingested antigens, and subsequent responses to antigen exposure via the airways.
PDL1 is not needed for peritoneal macrophage suppression of T cell activation (176.1)
Authors: Riggs James , Werda Amy , Cua Jackelyn , Walker Amanda , Bucknum Amanda 
Published: January 2023

Abstract
The myeloid suppression found in tumors can be modeled by studying peritoneal cavity (PerC) macrophages (Mϕs). The high % of Mϕs in the PerC inhibit the proliferation of C57BL/6J (WT) T cells by iNOS catabolism of arginine. PerC T cells from IFNγR-/- mice proliferate indicating that IFNγ drives suppression. IFNγ increases expression of molecules that can promote (B7) or inhibit (B7H1/PDL1) T cell activation. PDL1 was of particular interest as it is upregulated on Mϕs & has been reported to restrict T cell activation in tumors. B7-/-, PDL1-/-, & IFNγR-/- PerC cells were compared to those from WT mice. B7-/- mice had fewer CD4 & CD8 PerC T cells than WT. IFNγR-/- mice had fewer CD4 cells & more CD8 T cells than WT. PDL1-/- mice had fewer CD44hi & CD25+ CD4 T cells & more CD8 T cells, particularly CD44hi & GITR+ cells. B7-/- PerC T cells, like those of IFNγR-/- mice, were less suppressed & responded with PGE2 or IL-10 neutralization. However, they differed in that IL4, via arginase, regulated T cell proliferation in IFNγR-/- mice. Surprisingly like WT mice, PDL1-/- PerC T cells were suppressed by IFNγ-triggered iNOS. Although PDL1 costimulates IL10 production the absence of PDL1 did not increase IFNγ production. These results reveal a challenge for strategies intent on recovering immunity by blocking PDL1 in Mϕ-rich tumor microenvironments.
CD40 induced TCR revision promotes tolerance to self-antigen in Type I Diabetes pathogenic CD4+CD40+ T cells. (176.11)
Authors: Vaitaitis Gisela , Wagner David 
Published: January 2023

Abstract
Biomarkers for effector cells have been difficult to find, but we described a pathogenic CD4 T cell subset expressing CD40. We demonstrated that peripheral CD4+CD40+ T cells are necessary and sufficient to transfer autoimmune disease. Here we demonstrate that CD40 engagement of peripheral CD4+CD40+ T cells in-vitro renders those cells unable to transfer disease. We have shown that CD40 signals primary peripheral CD4+CD40+ T cells to access the recombination machinery that causes revision of TCR Vα. We demonstrate here that CD40 signals also causes revision of TCR Vβ. While this constitutes a mechanism that could result in the generation of autoaggressive T cells in the periphery, we demonstrate that this mechanism can be exploited for tolerizing autoaggressive T cells. We show that CD40 interacts directly with recombination machinery proteins RAG1, RAG2 and Ku-70 in CD4+CD40+ T cells and that CD40 becomes translocated to the nucleus upon CD40 stimulation. We also show that while CD40 can induce RAG1 and RAG2 expression, Fas signals act as a silencing mechanism. It will be important to further understand the involvement of CD40 in TCR revision in order to effectively target and tolerize autoaggressive T cells in autoimmune disease.
IL-10-independent regulatory role for B cells in suppressing autoimmunity through GITRL-mediated maintenance of Tregs (176.18)
Authors: Ray Avijit , Basu Sreemanti , Williams Calvin , Salzman Nita , Dittel Bonnie 
Published: January 2023

Abstract
A regulatory role for B cells has been shown in animal models of autoimmunity and several studies suggested an IL-10-dependent mechanism. In our model of experimental autoimmune encephalomyelitis (EAE), WT mice exhibited a monophasic disease and recovered, but B cell deficiency, either genetic (µMT) or anti-CD20-mediated, led to unresolved EAE. Although B cells regulated EAE, we did not detect IL-10-producing B cells. Hence, we investigated IL-10-independent roles for B cells in immune regulation. B cell deficiency resulted in reduced numbers of CD4+Foxp3+ T regulatory cells (Tregs) in the periphery, suggesting involvement of B cells in their peripheral homeostasis. Interestingly, B cell depletion therapy in humans has been associated with the onset of autoimmunity. Likewise, reduction of Tregs post anti-CD20-mediated depletion of B cells resulted in spontaneous EAE and accelerated colitis in genetically susceptible mice. To study B cell-Treg interactions, we transferred B cells into µMT mice, which resulted in the proliferation and partial restoration of Treg numbers, sufficient for the resolution of EAE. Mechanistically, expression of glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL) by B cells was required, but IL-10 and B7 molecules were dispensable. Our results demonstrate a novel IL-10-independent role for B cells in regulating autoimmunity by maintenance of Tregs via GITRL.
Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment (176.25)
Authors: Cohen Jarish , Fu Yang-Xin , Engelhard Victor 
Published: January 2023

Abstract
Lymphatic endothelial cells that reside in lymph nodes (LN-LEC) express peripheral tissue antigens, including the melanocyte differentiation protein tyrosinase, and induce deletional tolerance of tyrosinase-specific CD8 T cells. We have also recently shown that deletional tolerance is due to PD-L1 expressed by LN-LEC. To determine whether LEC from tissue lymphatic capillaries also have tolerogenic properties, we purified LEC from diaphragm (D-LEC) and colon (C-LEC). D-LEC and C-LEC express significantly less PD-L1 than LN-LEC, and express tyrosinase at levels insufficient to induce proliferation of tyrosinase-specific CD8 T cells in vitro. This suggested that cells and factors in the LN microenvironment induce the tolerogenic properties of LN-LEC. LEC from postnatal day 1 LN, which are severely lymphopenic, do not express PD-L1, but do so by day 7 when lymphocytes have colonized the LN. Adult LN contain 2 distinct LN-LEC subsets: PD-L1hi ICAM-1hi (LN-LEChi) and PD-L1int ICAM-1int (LN-LECint). Interestingly, tyrosinase expression and presentation is restricted to the LN-LEChi population. The representation and absolute number of LN-LEChi cells is reduced in Rag1-/- mice, µMT-/- (B cell-deficient) mice, and mice in which lymphotoxin β receptor (LtβR) signaling is blocked. Thus, LN-LEC are induced to express PD-L1 during the neonatal period, and B cells and LtβR signaling contribute to maintain a LN-LEC population that controls peripheral tolerance to tyrosinase.
Novel tissue regulatory role of IL-22 in human asthma (176.4)
Authors: Pennino Davide 
Published: January 2023

Abstract
BACKGROUND: Asthma is a chronic inflammatory disorder of the airways. Recently, IL-22 has been shown to mediate unclear anti-inflammatory effects in mouse models of lung inflammations. OBJECTIVE: To investigate the anti-inflammatory role of IL-22 in human asthma. METHODS: T cells derived from lung biopsies of asthmatic patients were characterized by flow cytometry. Human bronchial epithelial cells were stimulated with IL-22, IFNg or the combination of both cytokines, and their effects were investigated by whole genome analysis, ELISA and flow cytometry. The functional consequence of cytokine effects was evaluated by in vitro wound repair and T cell mediated cytotoxicity experiments. In vivo cytokine expression was measured by luminex in bronchioalveolar lavage fluids (BAL) of asthmatic patients. RESULTS: Th22 produce IL-22 during asthma. IFNg and IL-22 induced antagonistic responses on epithelial cells. IFNg antagonized IL-22 mediated wound closure while IL-22 impaired the expression of IFNg induced molecules such as MHC-I, MHC-II, CD54/ICAM-1, CCL5/RANTES, CXCL10/IP-10 and the CD8-mediated epithelial cell damage. Consistently, the IL22/IFNg ratio inversely correlated with the expression of CCL5/RANTES and CXCL10/IP-10 in BAL fluids of asthmatic patients. CONCLUSIONS: IL-22 is the first cytokine that act as anti-inflammatory by inhibiting IFNg pro-inflammatory effects on epithelial cells. IL-22 might be used to control the extent of IFNg mediated lung inflammation.
The IgM Fc receptor, FCMR, promotes B cell development and modulates antigen-driven immune responses (176.9)
Authors: Choi Seung-Chul , Wang Hongsheng , Tian Linjie , Murakami Yousuke , Shin Dong-Mi , Borrego Francisco , Morse Herbert , Coligan John 
Published: January 2023

Abstract
FCMR is a Fc receptor specific for pentameric IgM expressed at high levels by B cells. Although circulating IgM has profound effects on responses to pathogens, autoimmunity and B cell homeostasis, the biologic consequences of its binding to FCMR are poorly understood. We interrogated FCMR contributions to B cell function by studying mice lacking FCMR. FCMR transcripts are expressed at highest levels by follicular (FO) B cells and at much lower levels by developing B cells and other mature B cell subsets. FCMR-deficient mice have reduced numbers of developing B cells, splenic FO and peritoneal B-2 cells, but increased levels of peritoneal B-1a cells and autoantibodies. Following immunization, germinal center B cell and plasma cell numbers are increased. FCMR-deficient B cells are resistant to apoptosis induced by BCR ligation. Our studies demonstrate that FCMR functions are critical for B cell homeostasis, the prevention of autoreactive B cells and responsiveness to antigenic challenge.
Detection of auto-IgE in pediatric atopic eczema indicates autosensitization as an early immunological event. (177.12)
Authors: Seher Tanja , Mayer Johannes U. , Beck Helen , Brockow Knut , Traidl-Hoffmann Claudia , Ollert Markus , Ring Johannes , Gutermuth Jan , Schmidt-Weber Carsten B. 
Published: January 2023

Abstract
IgE-mediated allergies (e.g. asthma, atopic eczema [AE]) affect about 25% of western populations. Autoreactive IgE was detected in AE-patients and suspected to aggravate and chronify the disease. It is unclear, if autosensitization is a complication due to chronic allergic inflammation in adults or whether it is already present in children. Aims of this study were to develop a high-throughput assay for serologic detection of auto-IgE and to analyze if auto-IgE is organ-specific. We established an immunoassay to screen autoreactivity against whole cell protein extracts from primary keratinocytes (pKc) from non-AE and AE-patients, intestinal- and airway epithelial cells. After defining optimal conditions for all protein-extracts, we established a 384 well plate based immunoassay. We compared IgE-reactivity of 106 AE-patients (10mo.-70y.) and healthy controls on protein-extracts of all four cell types. 25% of AE-pts. showed IgE-autoreactivity against pKc from non-AE patients, 29% against pKc of AE-pts. and 33% against FHs74 Int. cells. Interestingly, the highest reactivity was detected in children. pKc from non-AE and AE-pts. bound more auto-IgE than HaCaT cells. This study identified auto-IgE at a similar level as reported previously. The IgE-specificity did not show organ-specificity, but auto-IgE seems to be an early immunological feature of AE in children. Current studies in birth-cohorts address the kinetics of auto-IgE-levels in relation to age and disease activity.
Global microRNA expression is essential for mast cell development in vivo (177.18)
Authors: Oh Sun-Young , Brandal Stephanie , Roers Axel , Zhu Zhou , Takemoto Clifford 
Published: January 2023

Abstract
microRNAs (miRNAs) are small, non-coding RNAs that have been shown to play a critical role in both normal physiology and disease, such as hematopoietic development and cancer. However, their role in mast cell function and development is unexplored. The RNaseIII endonuclease, Dicer, is required for the processing of pre-miRNAs into mature miRNAs. To investigate the role of global miRNA depletion on mast cells in vivo, we generated a mast cell-specific knock out of Dicer in mice. Transgenic mice (Mcpt5-Cre) that express Cre selectively in mast cells were crossed with mice containing the floxed conditional Dicer allele (Dicer f/f). Mice with both homozygous (Dicer -/-) and heterozygous (Dicer f/-) mast cell-specific deletion of Dicer were viable and healthy. However, Dicer -/- mice were found to have a profound mast cell deficiency with near complete loss of peritoneal, gastrointestinal, and skin mast cells. We examined the in vivo functional consequence of mast cell-specific Dicer deletion using an IgE-dependent passive systemic anaphylaxis (PSA) murine model. IgE sensitized wild type (Dicer f/f) and heterozygous (Dicer f/-) mice show marked hypothermia with antigen; however, homozygous (Dicer -/-) mice were completely unreactive to antigen challenge. These studies suggest a critical role for Dicer and miRNA expression for establishment of mast cell tissue compartments in vivo.
Mast cell specific negative regulation of LPS induced pro-inflammatory response by Itk and Btk (177.20)
Authors: Huang Weishan , Morales J. Luis , Gazivoda Victor P. , August Avery 
Published: January 2023

Abstract
Gram-negative bacterial endotoxin lipopolysaccharide (LPS) induces mast cell secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, which is responsible for septic hypothermia. The non receptor tyrosine kinases Itk and Btk are both expressed in mast cells, and act as signaling regulators, but their roles in the response of mast cells to LPS are unclear. Here we show that Itk/Btk double knockout (DKO) mice suffered exacerbated and prolonged LPS induced hypothermia with increased TNF-α production by mast cells, compared to WT, Itk-/- and Btk-/- mice. This aggravated LPS induced hypothermia was recapitulated in mast cell deficient Sash mice reconstituted with DKO bone marrow derived mast cells (BMMCs). LPS (TLR4 ligand) stimulated DKO BMMCs exhibited hyperactive pro-inflammatory cytokine production with severely altered NF-κB signaling, which was not observed with Pam3CSK4 (TLR1/2 ligand). By contrast, DKO bone marrow derived macrophage and dendritic cells were not hyper-responsive to LPS as observed in DKO BMMCs, suggesting that Itk and Btk act as mast cell specific negative regulators in LPS/TLR4 signaling. Microarray analysis further revealed that the absence of Itk and Btk in mast cells significantly enhanced LPS induced pro-inflammatory program, which could potentially deteriorate endotoxin induced mast cell mediated inflammatory diseases.
Expression of ADAM10 on mast cells: effects on IgE and stem cell factor activation (177.9)
Authors: Faber Travis , Fernando Josephine , Pullen Nicholas , Morales Johanna , Conrad Daniel , Ryan John 
Published: January 2023

Abstract
Mast cells are innate immune cells best characterized for their role in allergy. In response to cross-linking of the high-affinity IgE receptor, FcϵRI, mast cells release mediators such as histamine, leukotrienes, IL-6, and TNF-α. Additionally, mast cells are widely noted for their secreted proteases like chymases and cathepsins. We have decided to investigate the role that the protease A Disintegrin and Metalloproteinase 10 (ADAM10) plays on murine mast cells. To date, we have discovered mast cells express ADAM10 in vitro and in vivo, and that Treg cytokines TGF-β1 and IL-10 down regulate mast cell ADAM10. IL-10 effects depend on STAT3. ADAM10 deletion results in abrogated mast cell migration through Collagen IV to stem cell factor, but not to antigen. Also, ADAM10 deletion decreases IL-6 release post cross-linking, but does not alter other commonly released cytokines such as TNF-α, IL-13, and MIP-1α. Because of these findings, we hypothesize that ADAM10 plays a pro-inflammatory role in mast cell migration and also in allergic disease.
2P Imaging Reveals that PD-1 Induces Functional Exhaustion by Stabilizing Synapse Formation during Viral Persistence (178.16)
Authors: Zinselmeyer Bernd , Heydari Sara , Nayak Debasis , McGavern Dorian 
Published: January 2023

Abstract
Restoration of T cell function mediated by PD-1 blockade is a finding of great clinical relevance for the treatment of persistent infections and tumors. Presently, it is not known how PD-1 blockade improves the function of exhausted T cells. Infection of mice with an immunosuppressive strain of lymphocytic choriomeningitis virus (LCMV) is a well described model for T cell exhaustion. Here, we set out to gain novel insights into the mechanisms that underlie T cell exhaustion by imaging virus-specific CD8 and CD4 T cell responses to an acute versus persistent LCMV infection in the spleen using two-photon microscopy. Analysis of T cell dynamics in these two distinct environments revealed that T cell exhaustion during viral persistence is mediated by prolonged motility paralysis in the splenic marginal zone and red pulp - two regions where an abundance of viral antigen and PD-L1 was found. Importantly, we observed that intravenous injection anti-PD-1 enhanced anti-viral T cell motility in 30 minutes, which coincided with increased phosphorylation of ZAP-70 and ERK. Once T cells were released from infected targets, IFN-γ production significantly increased (within 1 hr), viral loads dropped by 70% (within 16 hrs), and mice ultimately developed fatal immunopathology (with 2-4 days). These data indicate that the PD-1 disables anti-viral CD8 and CD4 T cell signaling and function by stabilizing the synapse and holding them in a state of motility paralysis.
Effects of PD-1 signaling on the molecular control of T cell expansion (178.17)
Authors: Patsoukis Nikolaos , Brown Julia , Petkova Victoria , Liu Fang , Li Lequn , Boussiotis Vassiliki 
Published: January 2023

Abstract
Programmed death (PD)-1 is a potent T cell inhibitor critical for peripheral tolerance. Currently, it is unclear whether PD-1 has a global or a selective inhibitory effect on TCR signaling pathways involved in T cell expansion. It is also unclear how PD-1 affects the molecular machinery of cell cycle progression. Using primary human T cells we determined that PD-1 blocked cell cycle progression in the G1 phase. PD-1 did not alter the expression of G1 phase cyclins or cyclin-dependent kinases (Cdks) but, instead, suppressed transcription of the SCFSkp2 ubiquitin ligase that leads p27kip1 to degradation and resulted in accumulation of p27kip1. T cells receiving PD-1 signals displayed impaired Cdk2 activation and failed to phosphorylate Rb and Smad3 leading to suppression of E2F target genes but enhanced Smad3 transactivation. These events resulted in abrogation of the Cdk-activating phosphatase Cdc25A and upregulation of the Cdk4/6 inhibitor p15INK4. Suppression of Skp2 by PD-1 was mediated by inhibition of both PI3K/Akt and Ras/MEK/Erk pathways and was only partially reversed by IL-2, which restored activation of MEK/Erk but not Akt. In contrast to the inhibition of Ras and MEK/Erk pathway, PD-1 did not affect activation of Rap1, p38 and JNK MAP kinases. Thus, PD-1 selectively targets Ras/MEK/Erk and PI3K/Akt signaling to inhibit transcription of Skp2 and to activate Smad3 as an integral component of a pathway regulating blockade of cell cycle progression in T lymphocytes.
Vitamin D promotes Tr1 differentiation through the CD46 pathway (178.18)
Authors: Astier Anne , Kickler Karoline , Ni Choileain Siobhan 
Published: January 2023

Abstract
The complement regulator CD46 induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 activation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D has an immunomodulatory role and may be beneficial in several pathologies, including MS. Herein, we show that, upon CD46 costimulation, Vitamin D strongly increased the IL-10:IFNγ ratio, characteristic of the CD46-induced Tr1 phenotype. This was correlated with the modulation of several markers known to control T cell activation. Vitamin D strongly promoted the expression level of CD28, CD25 and CTLA-4 on CD46-activated T cells, while it concomitantly decreased CD46 expression. Importantly, addition of Vitamin D could restore the defective IL-10 production observed in T cells from patients with MS. Hence, Vitamin D promotes anti-inflammatory responses by mainly acting on CD46, and might be beneficial for T cell responses in MS.
Adoptive transfer of Regulatory T cells from burn-injured rats depressed T cell responses in the recipient sham rats (179.1)
Authors: Fazal Nadeem , Shelip Alla , Melaku Kalkidan , Bougher Ryan 
Published: January 2023

Abstract
Immunosuppression occurs after burn injury with or without septic complications. We hypothesize that CD4+CD25+ T cells (Treg) are responsible for transmitting inhibitory signals to the IL-2-producing T cells in burn related inflammatory/infectious conditions. Enriched Treg were obtained from day-3 burn rats by flow cytometry and magnetic microbead cell sorting and given intravenously to sham rats. The rats were then sacrificed day 1 and day 3 post-adoptive transfer and T cell proliferation responses were assessed by thymidine assay. The results indicated that when burn Treg were adoptively transferred to sham rats, T cell proliferation (CD4+, CD4+CD25+ and CD4+CD25-) of sham rats was significantly depressed. Furthermore, the results showed that adoptive transfer of Treg did not influence the phenotypic expression of CD4+ T cells of the recipient rats. The percentage expressions of CD25, CD11a (LFA), and CD62L of the recipient rats remained same as before adoptive transfer. Experiments are currently underway to expand these findings to burn plus septic rats. These preliminary findings however allow us to hypothesize that while burn injury alone can produce attenuated CD4+ T cell mediated responses as a result of actions of Treg; burn injury with septic complications may further cause an irreversible loss of T cell-mediated responses. The latter happening could be responsible for high morbidity and mortality in the injured host afflicted with burn plus a critical infection.