bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory T cells control CNS-infiltration of autoreactive T cells during viral infection without affecting the antiviral immune response (83.24)
Authors: Cervantes-Barragan Luisa , Firner Sonja , Züst Roland , Prodinger Carolin , Bechmann Ingo , Sparwasser Tim , Thiel Volker , Ludewig Burkhard 
Published: January 2023

Abstract
Regulatory T cells are essential for suppressing immune responses to autoantigens and therefore help to prevent autoimmunity. During viral infections in the CNS, an indiscriminate regulation of T cells can prevent autoimmune diseases but could also impair the control of viral replication. We analyzed here the impact of regulatory T cells in the control of T cell infiltration to the CNS, virus-induced CNS pathology, and viral clearance using the mouse hepatitis virus (MHV) A59 intranasal infection model; a virus infection that leads to encephalitis and demyelination. MHV infection of “depletion of regulatory T cell” (DEREG) mice, revealed that the lack of regulatory T cells during MHV infection leads to an increased T cell infiltration and pathology in the CNS. However, antiviral T cells response were not affected by the depletion of FoxP3+CD4+ T cells indicating that regulatory T cells control infiltration of T cells to the CNS without impairing or delaying the antiviral immune response. Moreover, in MHV infected mice, adoptively transferred-myelin oligodendrocyte glycoprotein (MOG35-50)-specific CD4+ T cells proliferated in cervical lymph nodes and migrated to the CNS, suggesting that MHV infection in the CNS induces the activation of self-reactive T cells which are controlled by regulatory T cells to reduce the risk of developing inflammatory CNS disease.
ST2 deficiency enhances the severity of Th1/Th-17 mediated inflammation (83.27)
Authors: Lukic Miodrag , Volarevic Vladimir , Mensah-Brown Eric , Shahin Allen 
Published: January 2023

Abstract
ST2 selectively and stably expressed on the surface of T-helper 2 (Th2) but not Th-1 cells is a ligand for recently identified Interleukin-33 (IL-33). We have studied the susceptibility to and severity of the two T cell mediated inflammatory process: multiple low dose streptozotocin induced diabetes and Con-A induced hepatitis, in ST2 deficient (ST2-/-) and “wild-type: BALB/C mice. After diabetes induction (40mg STZ/kg b.w. for 5 days) ST2-/- mice developed glycemia and glycosuria. β cell loss and intra-islet mononuclear infiltrates while “wild type” mice did not develop any biochemical signs and histology revealed only peri-insulitis. When injected with Con-A (12 mg/kg b.w) ST2-/- mice developed significantly enhanced hepatitis as evaluated by liver function test 8 and 24 hours after induction and quantitative analysis of the hepatocytes necrosis. Analysis of cellular make up of the pancreatic lymph nodes and pancreata (in diabetes) and liver infiltrating cells (in ConA induced hepatitis) and their cytokines content by FACS analysis and cytokine expression by RT-PCR revealed the enhanced infiltration of Th-1 and Th-17 cells and higher content and expression of proinflammatory cytokines: IFN-γ, IL-17 and TNF. We therefore concluded that attenuation of IL-33-ST2 axis facilitates the induction of Th-1/Th-17 mediated inflammatory autoimmunity.
Regulation of dendritic cell function and autoimmunity by microRNA-155 (83.29)
Authors: Lind Evan , Dissanayake Dilan , Ohashi Pamela 
Published: January 2023

Abstract
While many of the mechanisms that control self tolerance in the immune system have been discovered, there are many unanswered questions in understanding the molecular mechanisms that maintain immunological quiescence. The studies outlined here aims to examine how a newly discovered class of small RNA molecules called micro-RNA control one of the checkpoints limiting autoimmunity, namely the maturation state of dendritic cells. Micro-RNA are a class of non-protein coding RNA that act by binding the 3’ UTR end of messenger RNA and inhibiting translation. We have evidence implicating that one specific micro-RNA, miR-155, plays a role in maintaining self-tolerance in the immune system. We find that miR-155 levels increase in dendritic cells after maturation induced by TLR stimulation. In a new murine model of autoimmune diabetes developed in our lab, dendritic cells lacking miR-155 are unable to break immune tolerance to pancreatic islet cells antigens. Using this model we will investigate whether the lack of miR-155 in dendritic cells affects the induction and expansion of cytotoxic T lymphocytes as well as the pro-inflammatory response. Furthermore, we will also explore the targets that are regulated by miR-155 that mediate the induction of autoimmunity.
Mixed Chimerism with MHC-Matched Bone Marrow Transplantation Results in Dominant Protection From Autoimmune Diabetes (83.8)
Authors: Gill Ronald , Coulombe Marilyne , Toews Carrie , Yu Liping , Eisenbarth George 
Published: January 2023

Abstract
Allogeneic mixed chimerim can prevent disease onset in Type 1 diabetes. While bone marrow (BM) allografts from MHC-mismatched donors can prevent disease in NOD mice, levels of mixed chimerism can be variable and unstable. Also, MHC-mismatched BM usually involve donor T cell depletion, increasing risk for graft-versus-host reactivity. Therefore, we tested the ability of MHC-matched donors to protect NOD mice from disease. Young female NOD mice were irradiated (2 x 450R) and grafted with the following BM donors: (1) Disease-prone NOD (H-2g7), (2) MHC-matched, disease-resistant C57Bl/6.H-2g7 (B6.H-2g7), (3) MHC-mismatched, disease-resistant C57Bl/6 (B6), or (4) Mixtures of disease-prone + disease-resistant BM. Importantly, donor BM was depleted of mature T and B cells. Recipients of only NOD BM recapitulated diabetes in 31/33 (94%) recipients by 30 weeks. Conversely, recipients of B6.H-2g7 BM alone did not develop diabetes (0/26). Mixed NOD + B6.H-2g7 BM grafts resulted in marked disease protection in 27/30 recipients (p &lt;.001). However, recipients of mixed NOD + B6 BM grafts rejected the MHC-mismatched B6 donor and developed disease in 9/10 hosts (90%). Importantly, mixed NOD + B6.H-2g7 BM transplants resulted in remarkably stable, multi-lineage chimerism (&gt;40-50% NOD) for ≥ 30 weeks. Thus, MHC-matched BM allografts permits dominant disease protection and stable macro-chimerism in NOD mice. Also, disease-prone MHC is not an intrinsic barrier to autoimmune regulation.
BCR-induced actin rearrangement provides a driving force for the formation of surface BCR signalosomes (84.1)
Authors: Song Wenxia , Liu Chaohong , Miller Heather , Orlowski Gregory , Sharma Shruti , Lam Hui-King , Grooman Brian , Upadhyaya Arpita 
Published: January 2023

Abstract
In response to antigens, the BCR forms surface signalosomes where it initiates signaling cascades and antigen internalization. This study examines the role of the actin cytoskeleton in BCR signalosome formation. Both multi-valent soluble and membrane-associated antigens induce BCR clustering and actin reorganization. Actin is actively polymerized at BCR microclusters upon their formation and surrounding BCR clusters as they are merged into central clusters. Actin regulators, WASP, cofilin and gelsolin, are activated and recruited to BCR clusters. Latrunculin or jasplakinolide treatment, which blocks BCR-induced actin reorganization by depolymerizing or stabilizing F-actin, inhibits surface BCR clustering and B cell spreading. Jasplakinolide blocks antigen-triggered tyrosine phosphorylation. In contract, latrunculin alone, in the absence of antigenic stimulation, induces BCR microclustering and tyrosine phosphorylation, however, in a much slower kinetics than those induced by antigens. Btk deficiency inhibits not only antigen-induced actin polymerization, but also antigen-induced B cell spreading and BCR clustering. These results indicate that BCR-induced, Btk-dependent actin reorganization, consisting of temporospatially regulated actin polymerization and depolymerization, promotes the formation of surface BCR signalosomes by increasing the speed and the extend of BCR engagement and clustering. Our study reveals an actin-mediated positive feedback mechanism for BCR signaling.
Mice lacking IgA exhibit defective IgG antibody responses to polysaccharide conjugate vaccine (84.14)
Authors: Wilson-Welder Jennifer , Kirimanjeswara Girish , Metzger Dennis 
Published: January 2023

Abstract
Streptococcus pneumoniae is a leading cause of global disease. While capsular polysaccharide conjugate vaccines have decreased disease burden; a portion of the population remains unresponsive to vaccination. In order to understand the mechanisms responsible vaccine non-responsiveness, studies have been performed using mice with a targeted gene deletion that causes lack of IgA but few alterations in expression of other Ig isotypes. Surprisingly, IgA-/- mice were found nonetheless to exhibit specific defects in both IgA and IgG antibody responses to the polysaccharide (PS) component of pneumococcal conjugate vaccine. Neither IgM anti-PS responses nor IgG antibody responses to the protein component of the conjugate vaccine were affected. Furthermore, IgA-/- mice expressed fewer peritoneal B1a cells. As B1a and marginal zone B cells are considered to be the primary cell types that respond to polysaccharide antigens, this might to some extent explain the decreased anti-PS serum antibody titers seen in IgA-/- mice. Studies using bone marrow chimeras showed that reconstitution of IgA-/- mice with IgA+/+ B cells failed to restore antibody responsiveness to the PS component of the conjugate vaccine. Taken together, these results indicate that a defect in IgA expression affects B cell homeostasis, which is partially influenced by the environment that is present during B cell activation. (Supported by NIH grants RO1 41715 and R21 83878).
Anti-CD20 therapy alters immune tolerance by disrupting crosstalk between B cells and FoxP3+ Tregs (84.20)
Authors: Ray Avijit , Dittel Bonnie 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) thought to be due to dysregulation in immune responses. To study the regulatory role of B cells in CNS autoimmunity, we used the animal model of MS, experimental autoimmune encephalomyelitis (EAE), in which we demonstrated a regulatory role for B cells in the resolution of EAE using B cell deficient (μMT) mice. FoxP3+ T regulatory (Treg) cells have also been shown to suppress EAE. We have demonstrated a link between B cells expressing B7 and the presence of FoxP3+ Tregs in the CNS of mice with EAE, suggesting crosstalk between B cells and Tregs. To further study this crosstalk, we performed anti-CD20 depletion of B cells. Following B cell depletion, mice exhibited chronic disease as in μMT, but partial depletion of B cells resulted in resolution of EAE. We then investigated the role of B cells in the development, peripheral maintenance and function of Tregs. B cell depletion had no effect on Treg development or function. However, a significant reduction in the number of Tregs paralleled total B cell loss, whereas with partial B cell depletion Tregs were unaffected. Resolution of EAE and partial restoration of Treg numbers following B cell reconstitution provided further evidence of the importance of crosstalk between B cells and Tregs in immune regulation. These data suggest a role for B cells in regulating immune tolerance and controlling CNS autoimmunity by maintaining the number of Tregs.
GL7 antigen is expressed spatio-temporally selectively in rodent and human lymphocytes (84.21)
Authors: Laszlo Gloria , Balogh Andrea , Adori Monika , Matko Janos 
Published: January 2023

Abstract
GL7 was first described as a late activation antigen in mouse, expressed by pre- and immature B-cells, certain thymocytes, and used since as marker of germinal centers. Later GL7 was also found on some human cell lines and sialic acid residues (Sia) were identified as the critical part of the epitope. Enzymes involved in glycosylation show considerable differences between human and mouse and the specificity of some Sia-binding siglecs also vary between species. Here we investigated GL7 expression and membrane localization in rodent and human immunocytes and lymphoid tissues. Mouse and human cell lines, primary (resting and activated) mouse, rat and human lymphocytes were assayed with flow cytometry and confocal microscopy. Our results show that the GL7 epitope expression pattern is similar in rats and mice. In contrast, human lymphocytes selectively and constitutively express GL7, and its expression level can further increase or decrease upon activation of T and B lymphocytes, respectively. The correlation pattern between GL7 expression and binding of various lectins to the surface immunocytes further confirms that the α2,6-linked Neu5Ac is involved in the GL7 epitope in human, as well. The expressed GL7 epitope (possibly attached to protein or lipid molecules) is highly raft-associated in lymphoid cells. This and its spatio-temporally selective expression suggest possible regulatory or adhesion functions for the GL7 epitope-linked molecule(s) in human.
Inhibition of cyclooxygenase-2 activity impairs antibody production in human B cells and in mice infected with vaccinia virus (84.8)
Authors: Phipps Richard , Bancos Simona , Topham David , Chapman Timothy , Bernard Matthew 
Published: January 2023

Abstract
Generation of protective humoral immune responses against vaccines depends on optimal production of antibodies by B lymphocytes. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to curb undesirable symptoms of vaccination, including pain, fever and swelling. We previously demonstrated in B cells that cyclooxygenase-2 (Cox-2) is induced in response to both T-dependent and T-independent stimuli, including the TLR9 ligand CpG DNA, and that Cox-2 is crucial for antibody production. Expression of plasma cell transcriptional regulatory factors, including Blimp-1 and Xbp-1, were dependent on Cox-2 activity. Significantly fewer antibody secreting plasma cell precursors were generated in the presence of Cox-2 selective inhibitors, indicating that Cox-2 is essential for human B cell terminal differentiation. Cox-2 selective inhibitors were administered in vivo to determine the role of Cox-2 in a humoral immune response to live infection with vaccinia virus. Mice chronically treated with Cox-2 selective inhibitors produced less viral neutralizing IgG following live virus infection. Inhibition of Cox-2 resulted in a reduced frequency of IFN-γ producing T cells, indicating that T cell priming of B cells was attenuated. These data support the idea that impaired humoral immunity in the absence of Cox-2 activity can be dependent on both B cells and T cells and that the use of Cox-2 selective inhibitors have the potential to dampen humoral immunity to live virus infection and vaccines.
Loss of miR-181a-mediated DUSP6 repression increases the TCR threshold of naive CD4 T cells in the elderly (85.11)
Authors: Li Guangjin , Yu Mingcan , Lee Won-Woo , Weyand Cornelia , Goronzy Jorg 
Published: January 2023

Abstract
With increasing age, the ability of the immune system to respond to vaccination with a CD4 T cell response and the production of antibodies declines. The decline is only partially explained by a loss of naïve and central memory CD4 T cells due to thymic involution. Naïve CD4 T cells are present in sufficient, albeit compared to young adults reduced frequencies in most elderly suggesting that additional functional defects are important. In these studies, we compared naïve CD45RO- CD4+ T cells from 20 to 35 (n=117) and 70 to 85 (n=80) year-old healthy adults. Elderly T cells were less responsive to superantigen/dendritic cell (p&lt;0.001) stimulation. Signaling studies by PhosFlow showed reduced ERK (p&lt;0.0001), but normal ZAP70 phosphorylation in the first 5 minutes after stimulation, suggesting a selective age-related defect in the ERK pathway. In murine systems, DUSP6 has been implicated in differentiation-dependent TCR threshold calibration. In Western blot studies, DUSP6 protein was increased in elderly CD4 T cells (p=0.02), however, DUSP6 transcription was not different suggesting a defect in posttranscriptional regulation. Expression of miR-181a that binds to the DUSP6 3′UTR was decreased in elderly naïve CD4 T cells. Overexpression of miR-181a downregulated DUSP6 expression and restored ERK responses in elderly CD4 T cells. Our data suggest that loss of miR181a in naïve CD4 T cells increases the TCR threshold and contributes the immune defect in the elderly.
Selective regulation of glucocorticoid receptor translational isoforms in T cells and B cells (85.7)
Authors: Shin Soon Cheon , Schleimer Robert , Lu Nick 
Published: January 2023

Abstract
The glucocorticoid receptor (GR) has eight translational isoforms, each of which has a distinct ability to regulate gene expression and to mediate apoptosis. Little is known, however, about whether cell activation or differentiation alters the GR isoforms. We determined the pattern of GR isoform expression in purified human lymphocytes at rest and after activation with mitogens. Stimulation of T cells with ConA led to a slight increase in GR-A and induced a 3-5-fold increase in GR-C. In contrast, activation of B cells with CpG containing DNA did not alter the expression of GR isoforms. To determine the functional consequences of elevated GR-C in activated T cells, we screened the results of microarray studies of Jurkat cells expressing only single GR isoforms to search for genes that were selectively induced by glucocorticoids in cells expressing GR-C but not the other isoforms. We found seven genes that were selectively activated by dexamethasone (DEX) in GR-C-expressing cells and tested the influence of T cell activation on the ability of DEX to activate the expression of these genes. Two of the tested genes, AIM1 and TUBA3E, were significantly increased by DEX only in activated T cells, suggesting that induction of the GR-C isoform had enabled the glucocorticoid to alter the expression of these genes. These results suggest that activation of immune cells can lead to alterations in the expression of GR isoforms that modify the glucocorticoid-induced gene expression.
Promiscuous processing of human α/β-protryptases (86.13)
Authors: Le Quang , Gomez Gregorio , Zhao Wei , Min Hae-Ki , Fukuoka Yoshihiro , Katunuma Nobuhiko , Schwartz Lawrence 
Published: January 2023

Abstract
Human β-tryptase is stored in secretory granules of human mast cells as a heparin-stabilized homotetramer. Although β-protryptase is sequentially processed in vitro by autocatalysis at Arg-3 followed by cathepsin (CTS)-C proteolysis to the mature enzyme, CTSC-deficient mice effectively process the murine pro form of mast cell protease-6, a mouse tryptase. Tryptase processing activity(ies) distinct from CTSC were recognized in and partially purified from human HMC-1 cell extracts by ion exchange and gel filtration chromatography, and identified by LC-tandem mass spectroscopy to include CTSB and CTSL. Importantly, CTSB and CTSL could process α-protryptase (Q-3) and mutated β-protryptase (R-3Q) as well as β-protryptase, indicating no need for autocatalytic cleavage at Arg-3, whereas CTSC-dependent processing required the autocatalytic step. Heparin was required for processing and for tryptase tetramer formation, and also protected tryptase from degradation by CTSB and CTSL. Processed protryptases were tetrameric by gel filtration and mature by N-terminal sequence analysis. CTSL, CTSB and β-tryptase were co-localized to skin mast cell secretory granules based on their co-release upon degranulation, indicating that they traffic together within the mast cells. Thus, CTSL and CTSB may be central to the processing of both α and β protryptases in mast cells of human and perhaps other species, and are potential targets for attenuating production of mature tryptase.
TRPM7 kinase domain confers magnesium sensitivity to G-protein regulated mast cell degranulation (86.14)
Authors: Zierler Susanna , Ryazanova Lillia , Ryazanov Alexey , Penner Reinhold , Fleig Andrea 
Published: January 2023

Abstract
TRPM7 is a bi-functional protein where an ion channel domain is fused with an atypical α-kinase domain. Impairment of the kinase domain leads to hypomagnesemia and sensitization to allergic reactions. We here investigate whether TRPM7 is involved in receptor-stimulated peritoneal mast cell degranulation and histamine release. Using the whole-cell patch clamp technique, we find that mimicking hypomagnesemic conditions by removal of extracellular Mg2+ shifts the degranulation response to intracellular Ca2+ from a graded to an all-or-none process independent of functional TRPM7 activity. In contrast, G-protein-induced mast cell degranulation requires higher intracellular Ca2+ levels in cells isolated from a mouse heterozygotic for a TRPM7 kinase domain knock-out (dKhet). Removal of extracellular Mg2+ compensates for this effect by both significantly increasing the degranulation amplitude and accelerating the rate of secretion in dKhet but not wild type (wt) cells. These observations are confirmed in a histamine release assay, where G-protein induced histamine secretion using MIP-1α is greatly enhanced in dKhet mast cells under hypomagensemic conditions, whereas Ca2+-induced degranulation by FcϵRI crosslinking is similar compared to wt. We conclude that Ca2+-induced mast cell activation is sensitive to extracellular Mg2+ concentrations independent of TRPM7 and that the TRPM7 kinase domain, but not the channel domain, is involved in G-protein-regulated degranulation.
Basophils are transiently recruited into the draining lymph nodes during helminth infection via IL-3 but infection-induced Th2 immunity can develop without basophil lymph node recruitment or IL-3 (86.19)
Authors: Min Booki , Kim Sohee , Prout Melanie , Ramshaw Hayley , Lopez Angel , Le Gros Graham 
Published: January 2023

Abstract
Basophils are recognized as immune modulators through their ability to produce IL-4, a key cytokine required for Th2 immunity. It has also recently been reported that basophils are transiently recruited into the draining LN after allergen immunization and that the recruited basophils promote the differentiation of naïve CD4 T cells into Th2 effector cells. Likewise, basophils were recruited into the draining mediastinal and mesenteric LN at 3 and 10 days after infection with intestinal nematode Nippostrongylus brasiliensis, respectively. However, the recruitment was completely abolished in mice deficient in IL-3 or IL-3Rβ, suggesting that the IL-3/IL-3R system is absolutely required. Activated CD4 T cells appeared to be the primary source of IL-3. Experiments using bone marrow chimera strategy further revealed that the cell types expressing IL-3Rβ are of bone marrow origin. Unexpectedly, the lack of IL-3 or of basophil LN recruitment played little role in N. brasiliensis-induced Th2 immune responses as unaltered Th2 immune responses were observed in N. brasiliensis infected IL-3-/- mice. Consistent with these findings, basophil depletion in infected mice did not diminish the development of IL-4-producing CD4 T cells. Therefore, our results reveal a previously unknown role of IL-3 in recruiting basophils to the LN and demonstrate that basophils are not necessarily associated with the development of Th2 immunity during parasite infection.