bluuebunny/crossref_metadata_2025_split huggingface dataset:
The transcriptional regulator Bcl-3 impaires the function of regulatory T cells leading to the development of intestinal inflammation
Authors: Reissig Sonja , Nikolaev Alexei , Weigmann Benno , Gerlach Katharina , Glasmacher Elke , Hövelmeyer Nadine , Waisman Ari 
Published: January 2023

Abstract
The oncoprotein and transcription factor Bcl-3 (B cell leukemia-3) is a member of the IκB family of NF-κB inhibitors and was originally identified as a component of a chromosomal rearrangement in some B cell lymphomas. In contrast to other IκB proteins, Bcl-3 associates with p50 and p52 homodimers and is predominantly a nuclear protein involved in regulating nuclear NF-κB activity.
We could demonstrate that Bcl-3 plays a crucial role in the maintenance of Treg function as well as in the development of IBD. Data of patient cohorts illustrate that Bcl-3 expression levels correlate with activity of disease. Treatment of IBD patients with anti-TNFa therapy significantly reduced the expression of Bcl-3. To assess the role of Bcl-3 in IBD, we generated mice that overexpress Bcl-3 solely in T cells. Interestingly, these mice develop severe spontaneous colitis. This intestinal inflammation was not mediated by CD4+ T cells, which even display memory formation defects. Instead, we found that the development of disease is caused by an impaired function of Tregs and demonstrate that Bcl-3 regulates NF-κB activity intrinsically in Tregs. Our data emphasize a novel pathway in the maintenance of viability and suppressive function of Tregs in the gut that critically involves Bcl-3 as a negative regulator, qualifying this protein as an interesting pharmacological target for the treatment of IBD.
Suppression of acetylcholine receptor endocytosis in neuromuscular junction by carbonic anhydrase III in the pathogenesis of myasthenia gravis.
Authors: Huang shiqian , Zhao Xiaonan , Xu Congfeng 
Published: January 2023

Abstract
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifestated as fatigable muscle weakness. The disorder typically caused by pathogenic autoantibodies against the postsynaptic acetylcholine receptor in the endplate of skeletal muscle. Our previous studies have identified carbonic anhydrase III as a specific protein insufficient in skeletal muscle from myasthenia gravis patient. In this study, we determined to investigate the underlying mechanism how carbonic anhydrase III insufficiency contributes to myasthenia gravis. Based on experimental autoimmune myasthenia gravis animal model and myocyte C2C12 cells, we find that inhibition of carbonic anhydrase III promotes acetylcholine receptor, which is through lipid raft-mediated pathway, leading to accelerated degradation of surface acetylcholine receptor. While activation of carbonic anhydrase III negatively regulates acetylcholine receptor degradation, through suppressing the endocytosis of surface acetylcholine receptor, thus contributes to attenuation of myasthenia gravis. Further study demonstrates that carbonic anhydrase III regulates endocytosis of AChR through actin polymerization and Src phosphorylation. Collectively, our study illustrates that carbonic anhydrase III in skeletal muscle cells is critical for acetylcholine receptor homeostasis in neuromuscular junction, while carbonic anhydrase III deficiency induces accelerated degradation of acetylcholine receptor, leading to myasthenia gravis. This novel mechanism highlights the essential role of carbonic anhydrase III in regualtion acetylcholine receptor endocytosis, providing a potential therapeutic approaches for myasthenia gravis.
Leupaxin Regulates LFA-1 Related Function in Cytotoxic T Lymphocytes (CTL)
Authors: Yao Shugang , Ostergaard Hanne 
Published: January 2023

Abstract

Background
Leupaxin is an adaptor protein that functions downstream of integrin receptor engagement. It contains N-terminal LD domains and C-terminal LIM domains. Although leupaxin is primarily expressed in leukocytes, it is very little known about the localization and function in leukocytes.

Results
Degranulation follows the formation of the immunological synapse (IS) and recruitment of MTOC to the IS. Leupaxin co-localizes with MTOC and microtubules, and is recruited to the IS during CTL degranulation. Through deletion of leupaxin domains, it shows that both LD2 and LD4 domains are sufficient for leupaxin recruitment to the IS. Leupaxin fails to be recruited to the IS after deleting LD2–4 domains.
Leupaxin is a focal adhesion protein in adherent cells. Leukocytes do not form classical focal adhesions during migration. We have found that leupaxin is recruited to the contact zone during CTL migration on ICAM-1, and forms very dynamic focal adhesion (FA)-like structures. These structures are assembled in the leading edge, and disappear in the trailing edge. Leupaxin also co-localizes with vinculin and talin at the FA-like structures, which are both FA proteins. Different from the role of leupaxin at the IS, leupaxin C-terminal LIM domain contributes to the localization of leupaxin at the FA-like structures.

Conclusions
Leupaxin localization suggests that it contributes to LFA-1 related processes in CTL, including degranulation and migration, but with different domains. Leupaxin LD domains are necessary for the recruitment to the IS during degranulation, whereas LIM domains are necessary for the formation of FA-like structures during migration.
CD11c+ cells are required for lymphocyte trafficking into previously infiltrated pancreatic islets during type 1 diabetes.
Authors: Sandor Adam , Lindsay Robin S , Gebert Matthew , Bradley Brenda J , Haskins Kathryn , Jacobelli Jordan , Friedman Rachel Sharon 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a largely T cell mediated autoimmune disease that destroys the beta cells of the pancreatic islets. Initiation of T1D requires T cell activation in the pancreatic lymph node, and then activated T cells must enter the islets to destroy beta cells. The requirements for lymphocyte entry into islets are not fully understood. We show that lymphocyte entry into previously infiltrated islets is dependent on CD11c+ cells in the islets. T cells and B cells transferred prior to CD11c+ cell depletion were able to enter the islets; whereas, short-term CD11c+ cell depletion rapidly prevented further entry. CD11c+ cells are highly efficient antigen presenters; however, entry into the islets was not reliant on antigen for either activated or naïve T cells. An alternative role for CD11c+ cells in lymphocyte entry into the islets is the production of chemokines and cytokines, which can have direct chemotactic effects on lymphocytes or can activate vascular endothelium. CD11c+ cells in the islets express high levels of CXCL9, a chemoattractant for T and B lymphocytes. CXCR3, the receptor for CXCL9, is present on both T and B lymphocytes in the islets. We hypothesize that CD11c+ cells facilitate lymphocyte recruitment to the islets through a combination of chemokine production and activation of the islet vascular endothelium. Chemokine and cytokine production by CD11c+ cells may be targeted therapeutically for the treatment of T1D to prevent T cell entry into remaining or transplanted islets.
IL-15 stimulates core 2 O-glycan synthesis and regulates trafficking of memory CD8 T cells during viral skin infection
Authors: Mooster Jana L , Osborn Jossef , Khan Tahsin , Nolz Jeffrey 
Published: January 2023

Abstract
Following successful vaccination or pathogen clearance, recently activated CD8+ T cells that survive contraction differentiate into long-lived memory populations and provide host protection against re-infection. We have previously demonstrated that memory CD8+ T cells acquire the capacity to generate core 2 O-glycans in an antigen-independent manner, a post-translational modification required for binding to P- and E-selectin. In addition, we have shown that de novo synthesis of core 2 O-glycans can be regulated by IL-15 signaling and this modulates the ability for memory CD8+ T cells to traffic to inflamed tissues. Herein, we show that the trafficking of memory CD8+ T cells to Vaccinia Virus (VacV)-infected skin occurs in an antigen-independent manner, but that protective immunity requires antigen-specificity. Following epicutaneous infection with VacV, migratory dendritic cells express IL-15Rα, suggesting this cell type could trans-present IL-15 to T cells. In fact, nearly all memory CD8+ T cells in the draining lymph node during VacV infection synthesize core 2 O-glycans regardless of antigen specificity. IL-15 stimulates memory CD8+ T cells to specifically express ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (St3Gal4), an enzyme known to facilitate formation of sialyl Lewis X structures on core 2 O-glycans. Finally, we show that neutralizing IL-15 during VacV infection reduces E-selectin binding by circulating memory CD8+ T cells and results in decreased recruitment of these cells to the infected skin. Overall, these data identify IL-15 and core 2 O-glycan synthesis as critical regulators of memory CD8+ T cell trafficking to viral infection of the skin and perhaps other peripheral tissues.
CXCR4 mediates B-1 cell localization to the bone marrow and production of atheroprotective IgM antibody
Authors: Upadhye Aditi , McSkimming Chantel , Taylor Angela , McNamara Coleen 
Published: January 2023

Abstract
Existing evidence demonstrates that B1 cells exert protective effects in atherosclerosis through production of anti-inflammatory natural IgM antibodies that recognize oxidation-specific epitopes (OSE), such as MDA-LDL, present in diseased arteries. The bone marrow is a known niche for B1 antibody production. However, the mechanisms underlying B1 localization to the bone marrow and B1 antibody production are currently unclear. Our lab has correlated surface marker expression on peripheral blood mononuclear cells with clinical markers of atherosclerosis in a human cohort. Expression of the chemokine receptor CXCR4 on circulating B1 cells associates with decreased plaque burden in coronary arteries and increased plasma levels of anti-MDA-LDL IgM antibodies. To study the role of CXCR4 in modulating B1 cell function more directly, we generated mice with B cell-specific loss of CXCR4 (CXCR4BKO). 8-week-old CXCR4BKO mice demonstrate a significant reduction in B1 number in the bone marrow relative to littermate controls (CXCR4WT). No significant changes in B1 number were seen in the aorta, peritoneal cavity, or spleen. Using ELISA and ELISPOT, CXCR4BKO mice were demonstrated to have decreased circulating IgM levels and fewer IgM antibody-secreting cells (ASC) in the bone marrow, but not in spleen. CXCR4BKO and CXCR4WT mice were placed on 9 weeks Western diet (WD) or control chow diet and then analyzed for IgM ASC number. CXCR4WT WD-fed mice have increased IgM ASC’s in the bone marrow relative to CXCR4WTchow-fed controls. This increase did not occur in WD-fed CXCR4BKO mice. Our data demonstrate that CXCR4 mediates B1 localization to the bone marrow and IgM production in mice, and indicate an atheroprotective role for CXCR4 on B1 cells.
Multiplex Immunoassays for Simultaneous Quantification of Soluble Adhesion Biomarkers in Human and Mouse Samples
Authors: Sun Binggang , Yao Jingjing 
Published: January 2023

Abstract
Cells bind to each other or to the extracellular matrix via Cell Adhesion Molecules (CAMs). Most of the CAMs belong to four protein families, including the immunoglobulin superfamily (e.g., ICAM-1, VCAM-1 and ALCAM), the selectins (e.g., P-, E- and L-selectins), the cadherins (e.g., E-cadherin) and the integrins (e.g., LFA-1). CAMs control intercellular adhesion and mediate cell growth, migration, proliferation and apoptosis. As a result, they play important roles in a wide range of cellular and disease processes. The soluble forms of these CAMs have increasingly become popular biomarkers in various diseases including inflammatory disorders, cardiovascular diseases, wound repair and cancers. Therefore, accurate measurement of these biomarkers is critical for understanding disease progression and immune responses.
We have developed both human and mouse adhesion panels for simultaneous quantification of nine adhesion biomarkers, including ALCAM, ICAM-1, PECAM-1, VCAM-1, E-selectin, L-selectin, P-selectn, E-cadherin and ESM-1 (Endocan). Our multiplex panels are bead-based sandwich immunoassays using fluorescence-encoded beads that can be separated by a variety of flow cytometers. Both panels have been validated for use with cell culture supernatant, serum and plasma samples. Each antibody pair has been carefully selected for assay specificity, accuracy and reproducibility. Our assays exhibit low-pg/mL sensitivity, broad dynamic range over 4 orders of magnitude, and high precision with &lt;15% inter CV. No or negligible cross-reactivity was found for the analytes within each panel. In summary, our adhesion multiplex panels offer a reliable and efficient tool to help researchers advance our knowledge of these soluble CAMs.
SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1.
Authors: COTE Marjorie , Fos Camille , Canonigo-Balancio Ann Janette , Ley Klaus , Becart Stephane , Altman Amnon 
Published: January 2023

Abstract
SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca2+ signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and LFA-1 affinity maturation in CD4+ T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1. This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4+ T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT-deficient (Def6−/−) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling.
C-Myc regulation by Notch Signaling Modulates T Cell Differentiation
Authors: Song Jim Jianxun , Haque Rizwanul , Song Xinmeng , Lei Fengyang 
Published: January 2023

Abstract
Notch signaling is essential for T lineage commitment and further required during early phases of thymocyte differentiation. Active Notch signaling during early stages of T cell development inhibits other lineage potentials, such as B cell and myeloid cell (e.g., dendritic cell) potentials. However, the intracellular signaling pathways by which Notch signaling regulates T cell differentiation remain unknown. Here we show that the transcriptional factor c-Myc is controlled by Notch signaling which regulates T cell differentiation. In a well-established in vitro differentiation of T lymphocytes from stem cells, Notch signaling directly controls c-Myc expression. Overexpression of active c-Myc promotes while dominant-negative (dn) c-Myc inhibits early cell differentiation. Moreover, c-Myc expression mediated by Notch signaling modulates survivin, an inhibitor of apoptosis (IAP) protein, which is crucial for T cell development. Overexpression of active c-Myc increases while dn c-Myc reduces survivin expression, which corresponds to T cell differentiation within the in vitro differentiation system. These results identify c-Myc, together with survivin, as regulators of the differentiation of T cells from Notch signaling.
Temporal expression of Bim limits the development and repertoire of TCR+ double negative thymocytes and CD8αα intestinal intraepithelial lymphocytes.
Authors: Li Kun-Po , Fähnrich Anke , Roy Eron , Cuda Carla , Grimes H Leighton , Perlman Harris , Kalies Kathrin , Hildeman David A 
Published: January 2023

Abstract
DN T cells (CD4−CD8α−TCRαβ+) and CD8αα T cells compose a major lymphocyte population in the intestine and promote gut homeostasis. Their thymic development, i.e. agonist selection, has been shown to be controlled by the pro-apoptotic factor Bim. In addition to its role in the thymus, Bim also controls peripheral T cell survival. However, the role of Bim in thymic and peripheral homeostasis of DN T and CD8αα T cells remain unclear. Here, we found that T cell-specific expression of Bim during early, but not late, thymic development limits the levels of DN T and CD8αα T cells in the spleen and iIEL compartments. The loss of Bim altered the TCR repertoire of DN T cells, but not conventional CD4 or CD8 T cells. As IL-15 controls CD8αα cell homeostasis, and antagonizes Bim in other T cells, we examined whether the additional loss of Bim would restore CD8αα T cells in IL-15−/− mice. Strikingly, the additional loss of Bim restored splenic, but not intestinal, DN T and CD8αα T cells in IL-15−/− mice. Instead, IL-15 signaling via Stat5 synergized with TCR signaling in peripheral DN T cells to increase expression of CD8α. Furthermore, adoptive transfer of splenic DN T cells gave rise to CD8αα cells in immune intact recipients. Combined, these data show that Bim functions temporally to limit the development and TCR repertoire of CD8αα precursors in the thymus. Moreover, Bim limits IL-15-driven homeostasis of CD8αα cells in the secondary lymphoid organs; but does not restrict their IL-15-driven maturation that is critical for intestinal homeostasis.
Analysis of Ikaros tumor suppressor function in BCR-ABL1+ pre-B ALL reveals conserved target genes and biological pathways
Authors: Schjerven Hilde , Ayongaba Etapong Fonabei , McLaughlin Jami , Cheng Donghui , Eggesbø Linn Margrethe , Lindeman Ida , Park Eugene , Witte Owen N , Smale Stephen T , Frietze Seth , Muschen Markus 
Published: January 2023

Abstract
Inactivation of the transcriptional factor Ikaros (IKZF1) correlates with poor prognosis in progenitor B-cell acute lymphoblastic leukemia (pre-B ALL), and is a hallmark of the BCR-ABL1+ subgroup of pre-B ALL. Ikaros is a critical regulator of hematopoietic development and required for B-cell development, however the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. We analyzed recently developed mouse models of BCR-ABL1+ pre-B ALL containing targeted deletions of Ikaros DNA-binding zinc finger domains together with a new model of inducible expression of WT Ikaros in IKZF1-mutant human BCR-ABL1+ pre-B ALL. We found that both the mouse and human Ikaros-mutated leukemic cells displayed a less mature cell surface phenotype and failed to downregulate the developmentally restricted cell surface receptors c-kit and CD34, respectively. In addition, Ctnnd1, a gene that is also expressed in earlier hematopoietic progenitor cells and normally downregulated as cells differentiate down the B-cell lineage, was found to be a conserved Ikaros target gene, with increased expression in Ikaros-mutated leukemic cells. RNA sequencing defined the Ikaros target genes in both mouse and human Ikaros-mutated pre-B ALL cells and revealed additional conserved target genes and biological functions. Loss of Ikaros tumor suppression was associated with deregulated adhesion pathways and stem-cell signatures. Furthermore, our results presented herein suggest that Ikaros mediates tumor suppressor function, at least in part, by enforcing proper developmental-stage specific expression of multiple genes involved in a network of cadherin-dependent, Rho-regulated Wnt/b-catenin pathways.
Kainate receptor deficient mast cells exhibit increased activation in vivo and in vitro.
Authors: Elkovich Andrea , Sturgill Jamie L , Conrad Daniel H 
Published: January 2023

Abstract
Allergies and asthma are common ailments that are on the rise around the world, especially in young children. Mast cells play a direct role in the signs and symptoms characteristic in allergic patients. Kainate is an ionotropic member of the glutamate receptor family and is mainly studied in the brain. Recent investigations, however, have shown the presence of the Kainate Receptor (KAR) in peripheral tissues, including cells of the immune system. Our lab has previously studied the effects of KAR deficient mice and have found that these mice have reduced Th2 responses in a house dust mite extract model of allergic airway inflammation. We sought to determine if KAR deficient mast cells played a role in the phenotype observed. Paradoxically, these mast cells exhibited increased, rather than decreased mediator release in vitro by antigen–dependent degranulation. In vivo, KAR KO mice release significantly more histamine during a model of passive systemic anaphylaxis. Finally, KAR KO mice exhibit an exacerbated temperature drop in response to administered histamine. These results stand in contrast to the inhibition of the asthma model, but indicate that KAR agonist, rather than antagonist treatment of mast cells would be a treatment modality to decrease mast cell activation. Such studies are currently underway.
IL-10 enhances mast cell activation and is essential for the development of IgE-mediated experimental food allergy
Authors: Mathias Clinton B , Rovatti Jeffrey , Polukort Stephanie , Carlson Logan , Thompson Chelsea , Ser-Dolansky Jennifer , Kinney Shannon , Schneider Sallie S 
Published: January 2023

Abstract
IL-10 is a key pleiotropic cytokine that can both promote and curb Th2-dependent allergic responses. Herein we demonstrate a novel role for IL-10 in the development of IgE-mediated food allergy. Oral ovalbumin challenge in sensitized BALB/c mice resulted in a robust intestinal mast cell response accompanied by allergic diarrhea, mast cell activation and a predominance of Th2 cytokines, including enhanced IL-10 expression. In contrast, the development of intestinal anaphylaxis including diarrhea, mast cell activation, and Th2 cytokine production was significantly attenuated in IL-10−/− mice compared to WT controls. Furthermore, IL-10 directly promoted the activation of mast cells. Administration of IgE and antigen induced the development of passive anaphylaxis in WT mice, which was attenuated in IL-10−/− animals. However, treatment of IL-10−/− mice with recombinant IL-10 prior to IgE administration restored the development of passive anaphylaxis in these animals. Finally, adoptive transfer of WT mast cells restored allergic symptoms in IL-10−/− mice. Our observations demonstrate a critical role for IL-10 in driving mucosal mast cell activation, suggesting that in its absence, mast cell function is impaired, leading to attenuated food allergy symptoms.