bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Nephritogenic T Cell Response in Murine Chronic Graft-Versus-Host Disease
Authors: Meyers Catherine M. , Tomaszewski John E. , Glass Joan D. , Chen Clarice W. 
Published: December 2022

AbstractTo investigate mechanisms of cell-mediated events in chronic glomerulonephritis, T cell clones were isolated from kidneys of animals with murine chronic graft-vs-host disease. This systemic disorder is induced in normal (C57BL/6 × DBA/2)F1 recipients (H-2b/d) following transfer of parental (DBA/2) T cells (H-2d). These studies demonstrate that mouse renal (MR) T cells isolated from nephritic kidneys of diseased recipients are host-derived CD4+ α/β+ T cells. Adoptive transfer of a panel of MR clones to naive (C57BL/6 × DBA/2)F1 recipients reveals distinct functional subsets. One subset does not transfer renal disease, and one induces severe renal inflammation and damage. In vitro proliferative responses of nephritogenic MR clones reveal predominant reactivity toward autologous class II MHC (I-Ed/I-Ad) determinants, and selected nephritogenic MR clones preferentially recognize renal Ag preparations derived from normal (C57BL/6 × DBA/2)F1 kidneys. In addition, cytokine profile analysis of MR clones indicates a Th2 pattern with IL-4 and IL-10 expression, although nephritogenic T cell clones also express IFN-γ. These data suggest that the nephritogenic T cell response in chronic graft-vs-host disease is autoreactive in nature and may be restricted by determinants shared by both graft and host (Iad).
Analyses of Single B Cells by Polymerase Chain Reaction Reveal Rearranged VH with Germline Sequences in Spleens of Immunized Adult Rabbits: Implications for B Cell Repertoire Maintenance and Renewal
Authors: Sehgal Devinder , Schiaffella Enrico , Anderson Arthur O. , Mage Rose G. 
Published: December 2022

AbstractWe used PCR to amplify rearranged VHDJHgenes in single cells collected by micromanipulation from splenic germinal centers of immunized adult rabbits. In the course of the study, the objective of which was to analyze diversification of rearranged VHDJH sequences, we were surprised to find cells 7 and 10 days after immunization with rearranged VH1a2 as well as a-negative (y33 and x32) sequences that were identical or close to germline (10 or fewer changes). About 58% (82/140) of the sequences had unique CDR3 regions and were unrelated. In seven different germinal centers, we found one to four different clones with two to seven members. Clonally related cells underwent diversification by hypermutation and gene conversion. We found that contrary to published reports, adult rabbits indeed have newly diversifying B cell receptors in splenic germinal centers. The attractive idea that the rabbit, like the chicken, develops its B cell repertoire early in life and depends upon self-renewing cells in the periphery to maintain its B lymphocyte pool throughout life, is challenged by the current finding. Although a major population of B lymphocytes may be generated early in life, diversified extensively, and maintained by self-renewal in the periphery, some sources of cells with sequences close to germline do exist in adult rabbits and appear in the developing germinal centers. Although considerable repertoire diversity is generated in young rabbits, mechanisms for continued generation of B cell receptor diversity are retained in adult life, where they may confer survival advantage.
The Same Natural Ligand Is Involved in Allorecognition of Multiple HLA-B27 Subtypes by a Single T Cell Clone: Role of Peptide and the MHC Molecule in Alloreactivity
Authors: Paradela Alberto , García-Peydró Marina , Vázquez Jesús , Rognan Didier , López de Castro José A. 
Published: December 2022

AbstractThe human alloreactive CTL clone 27S69, raised against B*2705, cross-reacts with B*2702 and B*2703, but not with B*2701, B*2704, B*2706, or B*2710. Its natural epitope was identified by electrospray/ion trap mass spectrometry, as the proteasome-derived RRFFPYYV octamer. This is the first HLA-B27 ligand shown to be immunogenic in alloreactivity. The RRFFPYYVY nonamer, also found in the B*2705-bound peptide pool, was recognized much less efficiently, demonstrating that an alloreactive CTL distinguishes between very similar natural ligands. Molecular modeling suggested that this was due to the different conformation of each peptide in complex with B*2705. B*2702- and B*2703-RMA-S cells were lysed by CTL 27S69 when sensitized with the octamer, demonstrating that cross-reaction with these subtypes is through recognition of the same peptide as in B*2705. B*2704-, B*2706-, and B*2710-RMA-S cells were not sensitized for lysis, in spite of efficient binding of the octamer, indicating that polymorphism in these subtypes directly impairs allorecognition. B*2701-RMA-S and -C1R cells were sensitized for lysis by the octamer, suggesting lack of the endogenous peptide epitope on this subtype. Absence of the octamer in the B*2701-bound peptide pool further suggested that B*2701 polymorphism impairs the generation of this peptide.
Eliciting T Cell Immunity Against Poorly Immunogenic Tumors by Immunization with Dendritic Cell-Tumor Fusion Vaccines
Authors: Wang Jianli , Saffold Scott , Cao Xuetao , Krauss John , Chen Wei 
Published: December 2022

AbstractDendritic cells (DCs) are the most effective APCs and are being studied as natural adjuvants or Ag delivery vehicles to elicit T cell-mediated antitumor immunity. This study examined whether inoculation of DCs fused with poorly immunogenic tumor cells elicited tumor-reactive T cells for adoptive immunotherapy. DCs derived from bone marrow of C57BL/6 (B6) mice were fused with syngeneic B16 melanoma or RMA-S lymphoma cells by polyethylene glycol. The B16/DC and RMA-S/DC fusion hybrids expressed MHC class I, class II Ags, costimulatory molecules, as well as DC-specific and tumor-derived surface markers. The tumor/DC hybrids were capable of processing and presenting tumor-derived Ags, and immunization of B6 mice with irradiated B16/DC or RMA-S/DC vaccine elicited tumor-specific CTL activities. Vaccination of B6 mice with irradiated B16/DC fusion preparations induced partial host protective immunity against B16 tumor challenge. Reduced tumor incidence and prolonged survival time were observed. Adoptive transfer of T cells derived from B16/DC vaccine-primed lymph nodes into B16 tumor-bearing mice greatly reduced the number of established pulmonary metastases with or without in vivo administration of IL-2. Moreover, adoptive transfer of RMA-S/DC vaccine-primed, cultured lymph node T cells eradicated disseminated FBL-3 tumor. The results demonstrate that tumor/DC fusion products are effective cellular vaccines for eliciting T cell-mediated antitumor immunity.
Early IFN-γ Production and Innate Immunity DuringListeria monocytogenesInfection in the Absence of NK Cells
Authors: Andersson Åsa , Dai Wen Juan , Di Santo James P. , Brombacher Frank 
Published: December 2022

AbstractNK cells are believed to play a mandatory role during the early phases of Listeria monocytogenes infection by producing IFN-γ, which is required for the activation of macrophage effector functions. Mice deficient in the common cytokine receptor γ-chain (γc−/−), which completely lack NK cells, were used to examine whether NK cells were essential for resistance to Listeria infection in vivo. Surprisingly, infected γc−/− mice showed normal innate immunity and macrophage responses against sublethal Listeria infection 2 days postinfection. At this time point, γc−/− mice showed increased blood IFN-γ levels compared with those in noninfected controls, demonstrating an NK-independent source of IFN-γ, which explains early resistance. Listeria-infected γc−/− × recombinase-activating gene-2−/− double-deficient mice were unable to produce IFN-γ and were highly susceptible to L. monocytogenes. Since T cells, but not B cells, are major IFN-γ producers, and γc−/− T cells were found to be efficient IFN-γ producers in vitro, we conclude from these results that T cells functionally replace NK cells for the early IFN-γ production that is necessary for activating the innate immune system following infection with L. monocytogenes. This novel observation in listeriosis underscores how the adaptive immune response can maintain and influence innate immunity.
IL-1 Receptor Accessory Protein Is an Essential Component of the IL-1 Receptor
Authors: Cullinan Emily B. , Kwee Lia , Nunes Perla , Shuster David J. , Ju Grace , McIntyre Kim W. , Chizzonite Richard A. , Labow Mark A. 
Published: December 2022

AbstractThe recently described IL-1R accessory protein (IL-1R AcP) interacts with IL-1β and the IL-1 type-IR (IL-1RI), but an essential requirement for IL-1R AcP in IL-1 signaling in vitro has not been established and its role in vivo has not been examined. In this study, IL-1R AcP-deficient mice and fibroblasts were produced and characterized. All IL-1 agonists bound to IL-1R AcP-deficient cells through the type I IL-1R, but failed to activate gene expression through either the nuclear factor-κB or AP-1-dependent signaling pathways. Absence of IL-1R AcP differentially affected the affinity for IL-1 ligands. IL-1R AcP-deficient fibroblasts bound murine IL-1α and human IL-1R antagonist protein (IL-1Ra) with only moderately reduced affinity when compared with wild-type cells, whereas murine IL-1β affinity was reduced by 70-fold. IL-1 also failed to produce a biologic response in vivo in IL-1R AcP-deficient mice. These data demonstrate that a type I IL-1R/IL-1R AcP complex is required for signaling by all IL-1 agonists and for high affinity binding by IL-1β. Finally, IL-1R AcP is an essential signal transducing component of the functional IL-1R and should represent a novel target for blocking IL-1 function in human disease.
The Role of Leukocyte Emigration and IL-8 on the Development of Lipopolysaccharide-Induced Lung Injury in Rabbits
Authors: Yamamoto Toshihiro , Kajikawa Osamu , Martin Thomas R. , Sharar Sam R. , Harlan John M. , Winn2 Robert K. 
Published: December 2022

AbstractLeukocyte emigration and alveolar macrophage-derived cytokines may contribute to lung microvascular injury associated with adult respiratory distress syndrome. We have used mAbs against cell adhesion molecules on leukocytes (anti-CD18 and anti-CD49d) or against IL-8 to investigate these contributions. Intratracheal (i.t.) instillation of LPS (50 μg/kg) caused a significant increase in bronchoalveolar lavage polymorphonuclear leukocytes (PMNs) without an increase in mononuclear cells (MNCs) or an increase in lung permeability. Injection of LPS (10 μ/kg) i.v. at 24 h after i.t. LPS caused significant increases in bronchoalveolar lavage PMNs, MNCs, IL-8, and monocyte chemotactic protein-1, as well as increases in lung permeability. Rabbits that were administered i.t. LPS followed by i.v. LPS and treated with anti-CD18 mAb had a significantly lower lung permeability index and emigration of fewer PMNs but no change in MNC emigration compared with saline treatment. Anti-IL-8 mAb treatment resulted in a significantly lower lung permeability index with no change in PMN emigration compared with no treatment. These results suggest that PMN emigration is necessary but not sufficient for the development of LPS-induced lung injury, and that IL-8 plays a significant role in PMN-dependent lung injury, independent of PMN emigration.
Regulation of the High Affinity Receptor for IgE on Human Epidermal Langerhans Cells
Authors: Kraft Stefan , Weßendorf Jörg H. M. , Hanau Daniel , Bieber Thomas 
Published: December 2022

AbstractHuman epidermal Langerhans cells (LC) express variable amounts of the high affinity receptor for IgE (FcεRI); the strongest expression is characteristic of atopic dermatitis. The receptor is suggested to take part in the pathophysiology of this disease by acting as a link between aeroallergens and Ag-specific T cells in an IgE-mediated, delayed-type hypersensitivity reaction. In the present study we show that even in the absence of surface expression, normal LC maintain an intracellular pool of the α-chain of FcεRI (FcεRIα) of the same m.w. as the surface-bound FcεRIα that is able to bind significant amounts of IgE. The lack of surface expression is linked to the absence or very low expression of the γ-chain (FcεRIγ). Moreover, the amount of FcεRIα expressed at the cell surface significantly correlates with the amount of FcεRIγ. LC differentiation toward lymphoid dendritic cells is accompanied by the disappearance of transcripts for FcεRIα, but not for FcεRIγ. This leads to a rapid decrease in the intracellular and surface levels of FcεRIα, which cannot be influenced by IL-4, IgE, or other agents. Overall, our findings suggest that these mechanisms enable LC to be highly versatile APCs by rapidly adapting the surface level of FcεRI to distinct inflammatory environments.
Norepinephrine Accelerates HIV Replication Via Protein Kinase A-Dependent Effects on Cytokine Production
Authors: Cole Steve W. , Korin Yael D. , Fahey John L. , Zack Jerome A. 
Published: December 2022

AbstractTo explore the role of sympathetic nervous system activation in HIV pathogenesis, we examined the effect of the neuroeffector molecule norepinephrine (NE) on HIV-1 replication in quiescently infected PBMCs that were subsequently activated with Abs to CD3 and CD28. NE accelerated HIV-1 replication at concentrations ranging from 10−8 to 10−5 M. This effect could be mimicked by protein kinase A (PKA) activators (forskolin or dibutyryl-cAMP) and abrogated by β-adrenoreceptor antagonists or the PKA inhibitor rp-cAMP, indicating transduction via the adrenoreceptor signaling pathway. NE reduced cellular activation and altered the production of several HIV-modulating cytokines: IL-10 and IFN-γ were markedly suppressed; TNF-α, IL-1β, IL-2, IL-4, and IL-6 were mildly suppressed; and levels of IL-12 were not significantly altered. The addition of either exogenous IFN-γ or IL-10 abrogated the effect of NE on virus production. Thus PKA-dependent suppression of cytokine production appears to mediate the enhancement of HIV-1 replication by NE.
Growth Factor Receptor-Bound Protein 2 (Grb2) Association with Hemopoietic Specific Protein 1: Linkage Between Lck and Grb2
Authors: Takemoto Yoshihiro , Furuta Masaaki , Sato Mitsuru , Findell Paul R. , Ramble Wendy , Hashimoto Yasuhiro 
Published: December 2022

Abstract
To analyze the growth factor receptor-bound protein 2 (Grb2) signaling pathway in lymphoid cells, we used expression cloning to isolate the genes encoding proteins that associate with Grb2. We find that the Src homology 3 domains of Grb2 directly associate, in vitro and in vivo, with murine hemopoietic specific protein 1 (HS1), a protein identical to Lck-binding protein 1. Because HS1 associates with the p56lck and p59lyn tyrosine kinases in vitro and in vivo, and becomes tyrosine phosphorylated upon various receptor stimulations, our present data suggest that HS1 mediates linkage between Lck or Lyn and Grb2 in lymphoid lineage cells.
Qualitative Differences Between Naive and Memory T Cells Make a Major Contribution to the More Rapid and Efficient Memory CD8+ T Cell Response
Authors: Kedl Ross M. , Mescher Matthew F. 
Published: December 2022

AbstractCD8+ T cells are present at a higher frequency following a primary response, and these memory cells exhibit qualitative differences from naive cells. The importance of these differences vs increased precursor frequency in making a memory response more rapid and efficient has been unclear. Adoptive transfer of 2C TCR transgenic CD8+ T cells into normal recipients, followed by i.p. challenge with allogeneic P815 tumor, results in a long-lived memory population that includes both endogenous host CD8+ T cells and 2C cells. The 2C cells can be identified, using 1B2 mAb specific for the TCR, and thus used as an indicator of the properties of the memory cells. The memory cells have a heterogeneous surface phenotype, and their distribution in lymphoid organs, blood, and peripheral sites is distinct from that of naive cells. Upon rechallenge with Ag, memory cells access the peritoneal cavity much more rapidly than do naive cells (12 h vs 5 days). This appears to result from a requirement for naive cells to interact with Ag before they can efficiently migrate to inflammatory sites, while this is not required for memory cells. In addition, memory cells exhibit some cytolytic activity before rechallenge with Ag, and potent cytolytic activity is present in the peritoneal cavity within 12 h of rechallenge. Comparison of primary and memory responses in mice having similar frequencies of Ag-specific precursors demonstrated that the more rapid migration and the immediate effector function of at least some memory cells contribute very substantially to making a memory response at a peripheral site more rapid and efficient.
Anti-CD40L Accelerates Renal Disease and Adenopathy in MRL-lprMice in Parallel with Decreased Thymocyte Apoptosis
Authors: Russell Jennifer Q. , Mooney Thomas , Cohen Philip L. , MacPherson Bruce , Noelle Randolph J. , Budd Ralph C. 
Published: December 2022

AbstractThe CD40/CD40L (CD40 ligand) axis regulates several interactions between T cells and B cells. Blocking of CD40 engagement by CD40L inhibits Ig class switch by B cells as well as diminishes T cell response to an immunizing Ag. For these reasons, disruption of CD40/CD40L interactions by anti-CD40L administration or by genetic disruption of CD40L has ameliorated a variety of autoimmune conditions. More recent findings suggest that a direct signal can be transmitted to T cells via their expressed CD40L, which can costimulate proliferation with CD3 or promote germinal center formation. It is therefore possible that treatment with anti-CD40L Ab might produce a different outcome than observed in genetically CD40L-deficient mice. In this regard, we observe that in contrast to the genetic deletion of CD40L in MRL-lpr mice, which diminishes autoimmune disease but has little effect on adenopathy, administration of anti-CD40L to MRL-lpr mice accelerates both of these parameters. This difference appears to result from anti-CD40L actively delivering a signal that inhibits T cell apoptosis in lpr mice. This was confirmed by in vitro studies demonstrating that CD40L cross-linking on lpr thymocytes inhibited apoptosis and surface TCR down-modulation induced by CD3 ligation.
The Chemokine Monocyte Chemotactic Protein 1 Triggers Janus Kinase 2 Activation and Tyrosine Phosphorylation of the CCR2B Receptor
Authors: Mellado M. , Rodríguez-Frade J. M. , Aragay A. , del Real G. , Martín A. M. , Vila-Coro A. J. , Serrano A. , Mayor F. , Martínez-A. C. 
Published: December 2022

AbstractThe chemokines are a growing family of low m.w., 70- to 80-residue proinflammatory cytokines that operate by interacting with G protein-coupled receptors. Chemokines are involved in cell migration and in the activation of specific leukocyte subsets. Using the Mono Mac 1 monocytic cell line, we show that monocyte chemotactic protein 1 (MCP-1) triggers activation of the Janus kinase 2 (JAK2)/STAT3 pathway and CCR2 receptor tyrosine phosphorylation. Both Ca2+ mobilization and cell migration are blocked in Mono Mac 1 cells by tyrphostin B42, a specific JAK2 kinase inhibitor. Within seconds of MCP-1 activation, JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. This MCP-1-initiated phosphorylation and association to JAK2 is also observed in CCR2B-transfected HEK293 cells. In contrast, when a CCR2B Tyr139Phe mutant is expressed in HEK293 cells, it is not phosphorylated in tyrosine and triggers neither JAK2/STAT3 activation nor Ca2+ mobilization in response to MCP-1. These results implicate the tyrosine kinase pathway in early chemokine signaling, suggesting a key role for this kinase in later events.
IL-2 and IL-4 Double Knockout Mice Reject Islet Allografts: A Role for Novel T Cell Growth Factors in Allograft Rejection
Authors: Li Xian Chang , Roy-Chaudhury Prabir , Hancock Wayne W. , Manfro Roberto , Zand Martin S. , Li Yongsheng , Zheng Xin Xiao , Nickerson Peter W. , Steiger Jurg , Malek Thomas R. , Strom Terry B. 
Published: December 2022

AbstractT cell growth factors (TCGFs) play a critical role in allograft rejection by promoting the activation and proliferation of alloreactive T cells. To determine whether IL-2 and IL-4 are of quintessential importance in allograft rejection and to identify possible alternative TCGFs, we have bred IL-2−/− and IL-4−/− double knockout (DKO) mice and studied islet allograft rejection using the DKO mice as allograft recipients. Although mononuclear leukocytes from DKO mice did not mount a proliferative response in vitro in response to anti-CD3 stimulation, crude islet allografts were vigorously rejected by DKO mice (mean survival time 17 ± 7, n = 8) as compared with wild-type controls (mean survival time 13 ± 4, n = 7). Treatment of DKO mice with anti-CD3 or rapamycin markedly prolonged the islet allograft survival. An analysis of intragraft cytokine gene transcripts showed robust expression of IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not detected in either wild-type or DKO mice. Provision of exogenous IL-2, IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the common γc of IL-2 receptor, a shared essential signaling component by receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival of islet allografts in DKO mice. Hence, a T cell dependent allograft rejection enabled by rapamycin-sensitive signals or signals mediated by binding of the γc chain occurs in the absence of both IL-2 and IL-4. Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active role in supporting allograft rejection.
Resistance to Antigen-Induced Airway Hyperresponsiveness Requires Endogenous Production of IL-12
Authors: Keane-Myers Andrea , Wysocka Maria , Trinchieri Giorgio , Wills-Karp Marsha 
Published: December 2022

AbstractWe have demonstrated previously that susceptibility of murine strains to the development of allergic airway responses is associated with a type 2 cytokine pattern. In the present study, we examine the in vivo role of IL-12 in the immune response to allergen exposure in susceptible (A/J) and resistant (C3H/HeJ, C3H) strains of mice. OVA sensitization and challenge induced significant increases in airway reactivity in A/J mice as compared with their PBS-challenged controls, while no increases in airway reactivity were observed in OVA-challenged C3H mice. OVA exposure of A/J mice resulted in marked increases in the Th2 cytokines, IL-4 and IL-10, in the bronchoalveolar lavage fluid, whereas increases in IFN-γ were observed in C3H mice. Strikingly, anti-IL-12 mAb (1 mg/mouse) treatment resulted in threefold increases in airway reactivity in OVA-challenged resistant C3H mice, concomitant with significant increases in bronchoalveolar lavage levels of Th2 cytokines and decreases in IFN-γ. IL-12 depletion of C3H mice also suppressed OVA-specific serum IgG2a levels and increased both serum OVA-specific IgG1 and IgE levels. Blockade of endogenous IL-12 levels in susceptible A/J mice resulted in further augmentation of type 2 immune responses. These results demonstrate that endogenous production of IL-12 is essential for resistance to Ag-induced airway hyperresponsiveness, and furthermore, that dysregulation of IL-12 production may lead to the development of deleterious type 2 immune responses to inhaled allergens.