bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-1β Inhibits IFN-γ-Induced Class II MHC Expression by Suppressing Transcription of the Class II Transactivator Gene
Authors: Rohn Wolfgang , Tang Li Ping , Dong Yuanshu , Benveniste Etty N. 
Published: December 2022

AbstractClass II MHC Ags are critical for the initiation of immune responses by presenting Ag to T lymphocytes, leading to their activation and differentiation. The transcriptional activation of class II MHC genes requires the induction of the class II transactivator (CIITA) protein, a master regulator that is essential for both constitutive and IFN-γ-inducible class II MHC expression. The cytokine IL-1β has been shown to inhibit IFN-γ-induced class II MHC expression in various cell types. We investigated the underlying mechanism of this inhibitory effect of IL-1β using human astroglioma cell lines. Our findings demonstrate that IL-1β prevents the expression of class II MHC mRNA and protein upon treatment with IFN-γ. Furthermore, we demonstrate that IFN-γ induction of CIITA mRNA expression is inhibited by treatment of cells with IL-1β. IL-1β suppressed IFN-γ activation of the type IV CIITA promoter in astroglioma cells, indicating that the inhibitory influence of IL-1β is mediated by inhibition of CIITA transcription. IL-1β did not interfere with IFN-γ receptor signal transduction, since tyrosine phosphorylation, nuclear translocation, and DNA binding of STAT-1α to an IFN-γ activation sequence of the type IV CIITA promoter were not affected by IL-1β. As well, IL-1β treatment did not affect the ability of IFN-γ-induced interferon-regulatory factor-1 (IRF-1) to bind the IRF-1 element within the type IV CIITA promoter. This study suggests that IL-1β may play a role in regulating immunoreactivity by inhibiting transcription of the CIITA gene, thereby reducing subsequent class II MHC expression.
IL-13 Is a Key Regulatory Cytokine for Th2 Cell-Mediated Pulmonary Granuloma Formation and IgE Responses Induced bySchistosoma mansoniEggs
Authors: Chiaramonte Mónica G. , Schopf Lisa R. , Neben Tamlyn Y. , Cheever Allen W. , Donaldson Debra D. , Wynn Thomas A. 
Published: December 2022

AbstractSchistosoma mansoni egg-induced pulmonary granuloma formation is a cell-mediated inflammatory response associated with dominant Th2-type cytokine expression, tissue eosinophilia, and high levels of serum IgE. In the present study, we show that in vivo blockade of the Th2 cytokine IL-13, using soluble IL-13R α2-Fc fusion protein, significantly reduced the size of pulmonary granulomas in unsensitized as well as egg-sensitized mice. Blocking IL-13 also significantly reduced total serum IgE levels. Interestingly, however, IL-13 blockade did not affect the evolving egg-induced Th2-type cytokine response. IL-4, IL-5, as well as IL-13 responses were indistinguishable in control-Fc- and soluble IL-13R α2-Fc fusion protein-treated animals. The smaller granulomas were also phenotypically like the control Fc-treated mice, displaying a similar eosinophil content. Additional studies in IL-4-deficient mice demonstrated that IL-13 was produced, but at much lower levels than in wild-type mice, while IL-4 expression was completely independent of IL-13. Moreover, while granuloma formation was partially reduced in IL-4-deficient mice, blocking IL-13 in these animals almost completely abrogated granuloma development and the pulmonary eosinophilia, while it simultaneously increased IFN-γ production. Together, these data demonstrate that IL-13 serves as an important mediator of Th2-mediated inflammation and plays a role in eliciting IgE responses triggered by schistosome eggs.
Development of an Animal Model for Neurocysticercosis: Immune Response in the Central Nervous System Is Characterized by a Predominance of γδ T Cells
Authors: Cardona Astrid E. , Restrepo Blanca I. , Jaramillo Juan M. , Teale Judy M. 
Published: December 2022

AbstractNeurocysticercosis is the most common parasitic disease of the central nervous system worldwide. It is caused by the metacestode form of the helminth Taenia solium. Study of the immune response in the human brain has been limited by the chronic progression of the disease, the influence of corticosteroid treatment, and the scarcity of patients who undergo surgical intervention. To better understand the immune response and associated pathology in neurocysticercosis, a mouse model was developed by intracranial infection of BALB/c mice with Mesocestoides corti, a cestode organism related to T. solium. The immune response reveals the presence of abundant inflammatory infiltrates appearing as early as 2 days postinfection in extraparenchymal regions. In contrast, infiltration of immune cells into parenchymal tissue is significantly delayed. There is a natural progression of innate (neutrophils and macrophages), early induced (NK cells and γδ T cells), and adaptive immune responses (αβ T cells and B cells) in infected mice. γδ T cells are the predominant T cell population. A cell-mediated Th1 pathway of cytokine expression is evident in contrast to the previously described Th2 phenotype induced in the periphery.
Processing and Release of IL-16 from CD4+ But Not CD8+ T Cells Is Activation Dependent
Authors: Wu David M. H. , Zhang Yujun , Parada Nereida A. , Kornfeld Hardy , Nicoll John , Center David M. , Cruikshank William W. 
Published: December 2022

AbstractIL-16 is synthesized as a precursor molecule of 68 kDa (pro-IL-16) that is processed by caspase-3, a member of the IL-1 converting enzyme (ICE) family. This cleavage results in a 13-kDa carboxy terminal peptide, which constitutes the bioactive secreted form of IL-16. We have previously reported constitutive IL-16 mRNA expression and pro-IL-16 protein in CD4+ and CD8+ T cells. Although bioactive IL-16 protein is present in unstimulated CD8+ T cells, there is no bioactive IL-16 present in CD4+ T cells. Along these lines, unstimulated CD8+ T cells contain active caspase-3. In the current studies we investigated the regulation of IL-16 protein and mRNA expression in CD4+ T cells and determined the kinetics of secretion following stimulation of the TCR. CD4+ T cells release IL-16 protein following antigenic stimulation, and this release is accelerated in time by costimulation via CD28. However, CD3/CD28 costimulation did not alter IL-16 mRNA appearance or stability in either CD4+ or CD8+ T cells. The secretion of bioactive IL-16 from CD4+ T cells correlated with the appearance of cleavage of pro-caspase-3 into its 20-kDa active form. Thus, resting CD8+ T cells contain active caspase-3 that is capable of cleaving pro-IL-16, whereas CD4+ T cells require activation for the appearance of active caspase-3. The mechanism of release or secretion of bioactive IL-16 is currently unknown, but does not correlate with cellular apoptosis.
Processing of HIV-1 Envelope Glycoprotein for Class I-Restricted Recognition: Dependence on TAP1/2 and Mechanisms for Cytosolic Localization
Authors: Ferris Robert L. , Hall Christopher , Sipsas Nikolaos V. , Safrit Jeffrey T. , Trocha Alicja , Koup Richard A. , Johnson R. Paul , Siliciano Robert F. 
Published: December 2022

AbstractProcessing of viral proteins for recognition by CTL involves degradation of the proteins in the cytosol of an infected cell followed by transport of the resulting peptides into the endoplasmic reticulum (ER) by the TAP1/2 complex. Uncertainty exists over the site of processing of viral envelope (env) proteins since the extracellular domains of env proteins are not present in the cytosol where the class I Ag-processing pathway begins. Rather, the ectodomains of env proteins are cotranslationally translocated into the ER during biosynthesis. To analyze env protein processing, we used the herpes simplex virus protein ICP47 to block peptide transport by TAP1/2 and examined the effects of TAP blockade on the processing of the HIV-1 env protein. For the majority of env-specific CD8+ CTL, the processing pathway required TAP1/2-mediated transport of cytosolic peptides into the ER. To determine how env peptides are generated in the cytosol, we analyzed the processing of two TAP1/2-dependent epitopes containing N-linked glycosylation sites. In each case, processing involved glycosylation-dependent posttranslational modification of asparagine residues to aspartic acid. These results are consistent with cotranslational translocation of env into the ER, where glycosylation occurs. This is followed by export of a fraction of the newly synthesized protein into the cytosol, where it is deglycosylated, with conversion of the asparagines to aspartic acid residues. Following cytoplasmic proteolysis, env peptides are retransported by TAP1/2 into the ER, where association with class I occurs. Thus, the env protein can enter the class I pathway through multiple distinct processing mechanisms.
Lymphotoxin αβ Is Expressed on Recently Activated Naive and Th1-Like CD4 Cells but Is Down-Regulated by IL-4 During Th2 Differentiation
Authors: Gramaglia Irene , Mauri Davide N. , Miner Kent T. , Ware Carl F. , Croft Michael 
Published: December 2022

AbstractLymphotoxin (LT) is a cytokine that orchestrates lymphoid neogenesis and formation of germinal center reactions. LT exists as a membrane heterotrimer of α and β subunits and is secreted as a homotrimer, LTα3. Using LTβR.Fc, expression of LTαβ on CD4 T cell subsets was investigated in a TCR transgenic model. LTαβ was evident 24–72 h after activation of naive T cells with specific Ag, and declined thereafter. Early expression was independent of IFN-γ and IL-12, however, IL-12 prolonged expression. LTαβ was reinduced within 2–4 h after Ag restimulation, but declined by 24 h regardless of IL-12 or IFN-γ priming. Exposure of naive T cells to IL-4 did not affect early LTαβ expression at 24 h, but resulted in subsequent down-regulation. IL-4-differentiated Th2 effectors did not re-express LTαβ, and LTαβ was transiently found on Th1 clones but not Th2 clones. LTα3 and TNF were immunoprecipitated from supernatants and lysates of IL-12 primed cells but not IL-4 primed cells. These studies demonstrate that LTαβ is expressed by activated naive CD4 cells, unpolarized IL-2-secreting effectors, and Th1 effectors. In contrast, loss of surface LTαβ and a lack of LTα3 and TNF secretion is associated with prior exposure to IL-4 and a Th2 phenotype.
TCR, LFA-1, and CD28 Play Unique and Complementary Roles in Signaling T Cell Cytoskeletal Reorganization
Authors: Sedwick Caitlin E. , Morgan Margaret M. , Jusino Lismaida , Cannon Judy L. , Miller Jim , Burkhardt Janis K. 
Published: December 2022

AbstractT cells interacting with APCs undergo rearrangement of surface receptors and cytoskeletal elements to face the zone of contact with the APC. This polarization process is thought to affect T cell signaling by organizing a specialized domain on the T cell surface and to direct T cell effector function toward the appropriate APC. We have investigated the contribution of TCR, CD28, and LFA-1 signaling to T cell cytoskeletal polarization by assaying the response of an Ag-specific Th1 clone toward a panel of transfected APCs expressing MHC class II alone or in combination with ICAM-1 or B7-1. We show that polarization of talin, an actin-binding protein, occurs in response to integrin engagement. In contrast, reorientation of the T cell microtubule-organizing center (MTOC) is dependent on and directed toward the site of TCR signaling, regardless of whether integrins or costimulatory molecules are engaged. MTOC reorientation in response to peptide-MHC complexes is sensitive to the phosphatidylinositol 3-kinase inhibitor wortmannin. CD28 coengagement overcomes this sensitivity, as does activation via Ab cross-linking of the TCR or via covalent peptide-MHC complexes, suggesting that phosphatidylinositol 3-kinase is not required per se but rather plays a role in signal amplification. Engagement of TCR in trans with LFA-1 results in separation of MTOC reorientation and cortical cytoskeletal polarization events, indicating that the two processes are not directly mechanistically linked. These studies show that T cells mobilize individual cytoskeletal components in response to distinct and specific cell surface interactions.
Monocytes Stimulate Expression of the Bcl-2 Family Member, A1, in Endothelial Cells and Confer Protection Against Apoptosis
Authors: Noble Karen E. , Wickremasinghe R. Gitendra , DeCornet Chris , Panayiotidis Panayiotis , Yong Kwee L. 
Published: December 2022

AbstractWe have investigated the molecular mechanisms underlying the ability of peripheral blood monocytes to block apoptosis induction in endothelial cells. Monocytes stimulated the expression of the bcl-2 homologue A1 in serum-starved endothelial cells after 6 h of coincubation, with elevated A1 levels persisting for up to 21 h. IL-1 and TNF also stimulated A1 expression at 6 h, but A1 transcript levels fell by 21 h. Direct cellular contact with monocytes was required for stimulation of A1 mRNA in endothelial cells. Stimulation of endothelial cell A1 mRNA by monocytes was not inhibited by anti-β2 integrin Abs, but anti-platelet endothelial cell adhesion molecule-1 (PECAM-1) mAb reduced A1 transcript levels at 21 h. Studies employing either TNF on its own, or anti-TNF in endothelium/monocyte cocultures showed that TNF plays a role in the early (6-h) stimulation of A1, but is less important for the sustained elevation of A1 levels at 21 h. Serum-starved endothelial cells demonstrated increased survival and decreased apoptosis after coculture with monocytes. IL-10 reduced A1 mRNA expression in, as well as survival of, endothelial cells that were cocultured with monocytes. In comparison with A1, Bcl-2 was expressed at low levels and was up-regulated by monocytes only at 21 h, while neither Bax nor Bcl-xL levels were altered by monocytes. The interaction of monocytes with endothelium during the course of an inflammatory reaction may provide survival signals to endothelial cells.
Distinct Effects of Jak3 Signaling on αβ and γδ Thymocyte Development
Authors: Eynon Elizabeth E. , Livák Ferenc , Kuida Keisuke , Schatz David G. , Flavell Richard A. 
Published: December 2022

AbstractJanus kinase 3 (Jak3) plays a central role in the transduction of signals mediated by the IL-2 family of cytokine receptors. Targeted deletion of the murine Jak3 gene results in severe reduction of αβ and complete elimination of γδ lineage thymocytes and NK cells. The developmental blockade appears to be imposed on early thymocyte differentiation and/or expansion. In this study, we show that bcl-2 expression and in vivo survival of immature thymocytes are greatly compromised in Jak3−/− mice. There is no gross deficiency in rearrangements of the TCRδ and certain γ loci in pre-T cells, and a functional γδ TCR transgene cannot rescue γδ lineage differentiation in Jak3−/− mice. In contrast, a TCRβ transgene is partially able to restore αβ thymocyte development. These data suggest that the signals mediated by Jak3 are critical for survival of all thymocyte precursors particularly during TCRβ-chain gene rearrangement, and are continuously required in the γδ lineage. The results also emphasize the fundamentally different requirements for differentiation of the αβ and γδ T cell lineages.
Interaction of Murine MHC Class I Molecules with Tapasin and TAP Enhances Peptide Loading and Involves the Heavy Chain α3 Domain
Authors: Suh Woong-Kyung , Derby Michael A. , Cohen-Doyle Myrna F. , Schoenhals Gary J. , Früh Klaus , Berzofsky Jay A. , Williams David B. 
Published: December 2022

AbstractIn human cells the association of MHC class I molecules with TAP is thought to be mediated by a third protein termed tapasin. We now show that tapasin is present in murine TAP-class I complexes as well. Furthermore, we demonstrate that a mutant H-2Dd molecule that does not interact with TAP due to a Glu to Lys mutation at residue 222 of the H chain (Dd(E222K)) also fails to bind to tapasin. This finding supports the view that tapasin bridges the association between class I and TAP and implicates residue 222 as a site of contact with tapasin. The inability of Dd(E222K) to interact with tapasin and TAP results in impaired peptide loading within the endoplasmic reticulum. However, significant acquisition of peptides can still be detected as assessed by the decay kinetics of cell surface Dd(E222K) molecules and by the finding that prolonged viral infection accumulates sufficient target structures to stimulate T cells at 50% the level observed with wild-type Dd. Thus, although interaction with tapasin and TAP enhances peptide loading, it is not essential. Finally, a cohort of Dd(E222K) molecules decays more rapidly on the cell surface compared with wild-type Dd molecules but much more slowly than peptide-deficient molecules. This suggests that some of the peptides obtained in the absence of an interaction with tapasin and TAP are suboptimal, suggesting a peptide-editing function for tapasin/TAP in addition to their role in enhancing peptide loading.
In Vivo IL-12 Production and IL-12 Receptors β1 and β2 mRNA Expression in the Spleen Are Differentially Up-Regulated in Resistant B6 and Susceptible A/J Mice During Early Blood-StagePlasmodium chabaudiAS Malaria
Authors: Sam Hakeem , Stevenson Mary M. 
Published: December 2022

AbstractAs previously reported, blood-stage Plasmodium chabaudi AS malaria is lethal by days 10–12 postinfection in susceptible A/J mice that mount an early, predominantly Th2 response. In contrast, resistant C57BL/6 (B6) mice clear the infection by 4 wk with an early Th1 response. In this study, we analyzed in vivo production of IL-12, a potent Th1-inducing cytokine, during the first 5 days after P. chabaudi AS infection in these mice. By day 2, serum IL-12 p70 levels were significantly increased in B6 mice over basal levels and were also significantly higher compared with A/J mice that showed no significant changes in serum p70 levels after infection. Splenectomy of resistant B6 mice before infection demonstrated that the spleen is the major source of systemic IL-12 in these hosts. Splenic mRNA levels of both p40 and p35 were significantly higher in A/J mice; however, the ratios of p40/p35 mRNA levels were similarly up-regulated in both strains. Furthermore, B6 but not A/J mice showed significant up-regulation of splenic IL-12R β2 mRNA over basal levels by days 3 and 4, coincident with sustained up-regulation of splenic IFN-γ mRNA levels on days 3–5. However, IL-12R β1 mRNA levels in the spleen were similarly up-regulated in both mouse strains by day 3. Taken together, these data suggest that high systemic IL-12 production, accompanied by an early and sustained up-regulation of both IL-12R β1 and β2 mRNA levels in the spleen, as occurs in resistant B6 mice, appears to preferentially induce protective Th1 responses against blood-stage malaria.
Biased TCR Repertoire in Infiltrating Lesional T Cells in Human Bancroftian Filariasis
Authors: Freedman David O. , Plier David Adam , Almeida Adriana de , Miranda Janaina , Braga Cynthia , Maia e Silva Maria C. , Tang Jianming , Furtado Andre 
Published: December 2022

Abstract
To investigate the hypothesis that T cells recognizing specific Ags localize to the site of disease activity in human bancroftian filariasis, we have compared the repertoire of TCR Vβ gene segments in lesions vs blood in individual patients by RT-PCR ELISA. Vβ14 and Vβ24 were overrepresented (5% greater in tissue compared with PBMCs and/or tissue/PBMC ratios in the highest 5% of all tissue/PBMC ratios for all Vβs for all subjects) in 50% and 40% of study subjects, respectively. Overrepresentation of these two Vβs did not occur in any control subject. In comparing three patient groups, the proportion of individuals meeting at least one criterion for Vβ14 overrepresentation was shown to increase in tandem with our current concepts of disease progression (asymptomatic filariasis = 25%; clinical filariasis with active infection = 60%; clinical filariasis without active infection = 71%). In 6 of the 10 individuals with Vβ14 overrepresentation, Vβ14 represented &gt;20% of the entire lesional Vβ repertoire. All but one of the 20 study subjects had at least one Vβ gene segment that was overrepresented in tissue compared with PBMCs. Only a small number of Vβs, usually three or less, were overrepresented in any single filariasis patient. However, in the same tissue, no differences between patient groups were found when IFN-γ, TNF-α, IL-4, IL-5, and IL-12 mRNA expression were examined. Taken together, these findings suggest that, in principle, in essentially all patients, whether with subclinical or with clinical filariasis, distinct and limited T cell populations are concentrated in affected tissue.
Cutting Edge: Clustered AU-Rich Elements Are the Target of IL-10-Mediated mRNA Destabilization in Mouse Macrophages
Authors: Kishore Raj , Tebo Julie M. , Kolosov Mikhail , Hamilton Thomas A. 
Published: December 2022

AbstractIn the present study we show that IL-10-mediated inhibition of inflammatory gene expression can be mediated by an AU-rich element (ARE) cluster present in the 3′ untranslated region (3′UTR) of sensitive genes. A series of chloramphenicol acetyl transferase (CAT) reporter gene constructs were prepared in which different fragments from the IL-10-sensitive KC mRNA 3′UTR were placed downstream of the coding region of the reporter gene CAT. CAT mRNA containing the KC 3′UTR was markedly destabilized as compared with the control CAT mRNA, and the decay rate was further increased in cells stimulated with IL-10. The KC 3′UTR contains an ARE cluster and three isolated ARE motifs. The ARE cluster spanning nucleotides 378–399 appeared to be both necessary and sufficient to mediate sensitivity to IL-10 because a 116-nucleotide fragment that contains the cluster conferred sensitivity, while mutation of the sequence between positions 378 and 399 eliminated sensitivity. The destabilizing effect of IL-10 was relatively selective, as the stability of chimeric CAT mRNAs was not modulated in cells treated with IFN-γ or IL-4.
N-Acetyl-l-Cysteine Inhibits Primary Human T Cell Responses at the Dendritic Cell Level: Association with NF-κB Inhibition
Authors: Verhasselt Valérie , Vanden Berghe Wim , Vanderheyde Nathalie , Willems Fabienne , Haegeman Guy , Goldman Michel 
Published: December 2022

Abstract
N-acetyl-l-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-κB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.