bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial Agonist Effect Influences the CTL Response to a Heterologous Dengue Virus Serotype
Authors: Zivny Jaroslav , DeFronzo Matthew , Jarry William , Jameson Julie , Cruz John , Ennis Francis A. , Rothman Alan L. 
Published: December 2022

AbstractActivation of dengue serotype-cross-reactive memory CTL during secondary dengue virus (DV) infection is thought to be important in the pathogenesis of dengue hemorrhagic fever. To model this effect, we studied the CTL responses to DV types 2 (D2V) and 3 (D3V) in PBMC from an individual previously infected with D3V. DV-specific CD8+ CTL from this donor recognized two HLA-B62-restricted epitopes on the NS3 protein, aa 71–79 (SVKKDLISY) and 235–243 (AMKGLPIRY). Both D3V-specific and D2V/D3V-cross-reactive CTL clones were detected for each epitope; all D2V-reactive CTL clones could lyse D2V-infected autologous cells. CTL responses to both epitopes were detected in bulk cultures stimulated with D3V, but PBMC stimulated with D2V recognized only the 235–243 epitope. IFN-γ enzyme-linked immunospot assay showed that the D2V (71–79) peptide (DVKKDLISY) did not efficiently activate T cells. Analysis of a CTL clone suggests that the D2V (71–79) peptide acts as a partial agonist, able to sensitize target cells for lysis and inducing only minimal proliferation at high concentrations. These results suggest that variant peptide sequences present in the heterologous DV serotype can influence the CTL response in vivo during secondary DV infection.
Altered Immune Responses and Susceptibility toLeishmania majorandStaphylococcus aureusInfection in IL-18-Deficient Mice
Authors: Wei Xiao-qing , Leung Bernard P. , Niedbala Wanda , Piedrafita David , Feng Gui-jie , Sweet Matt , Dobbie Lorraine , Smith Andrew J. H. , Liew Foo Yew 
Published: December 2022

AbstractIL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (−/−) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/−) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18−/− mice are uniformly susceptible. The infected IL-18−/− mice produced significantly lower levels of IFN-γ and larger amounts of IL-4 compared with similarly infected +/− and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18−/− mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-γ and TNF-α synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory cytokines, and therefore could be an important target for therapeutic intervention.
A Novel Function of IL-12p40 as a Chemotactic Molecule for Macrophages
Authors: Ha Sang Jun , Lee Chu Hee , Lee Seong Beom , Kim Chang Min , Jang Kyung Lib , Shin Hee Sup , Sung Young Chul 
Published: December 2022

AbstractIL-12p70 plays a pivotal role in regulating the Th1/Th2 balance in the initial stage of immune responses. In contrast, IL-12p40, which is produced excess over IL-12p70, has been known to down-regulate IL-12p70-mediated responses by acting as an antagonist. To investigate in vivo function of IL-12p40, RH7777 rat hepatoma cells were engineered to inducibly express mouse IL-12p40 under the tight control of doxycycline (dox). In the absence of dox, s.c. injection of these cells into syngeneic rat was shown to generate tumors. However, the induction of IL-12p40 by dox was sufficient for inhibiting tumor formation, as well as for tumor regression. Immunohistochemical analysis showed that macrophages, but not CD4+ T, CD8+ T, and NK cells, were predominantly recruited into tumor sites as early as 3 days after IL-12p40 induction. These results were further supported by the observation that IL-12p40, but not C-terminal deletion mutants by more than 5 amino acids, was able to chemoattract peritoneal macrophages in vitro, suggesting that IL-12p40, when produced in a large excess over IL-12p70 in vivo, can initially amplify the immune responses against tumors by directly recruiting macrophages. Our findings indicate that IL-12p40 may function as an effector molecule as well as an antagonist of IL-12p70.
Role of the Stress Kinase Pathway in Signaling Via the T Cell Costimulatory Receptor 4-1BB
Authors: Cannons Jennifer L. , Hoeflich Klaus P. , Woodgett James R. , Watts Tania H. 
Published: December 2022

Abstract4-1BB is a member of the TNFR superfamily expressed on activated CD4+ and CD8+ T cells. 4-1BB can costimulate IL-2 production by resting primary T cells independently of CD28 ligation. In this study, we report signaling events following 4-1BB receptor aggregation using an Ak-restricted costimulation-dependent T cell hybridoma, C8.A3. Aggregation of 4-1BB on the surface of C8.A3 cells induces TNFR-associated factor 2 recruitment, which in turn recruits and activates apoptosis signal-regulating kinase-1, leading to downstream activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). 4-1BB ligation also enhances anti-CD3-induced JNK/SAPK activation in primary T cells. Overexpression of a catalytically inactive form of apoptosis signal-regulating kinase-1 in C8.A3 T cells interferes with activation of the SAPK cascade and with IL-2 secretion, consistent with a critical role for JNK/SAPK activation in 4-1BB-dependent IL-2 production. Given the ability of both CD28 and 4-1BB to induce JNK/SAPK activation, we asked whether hyperosmotic shock, another inducer of this cascade, could function to provide a costimulatory signal to T cells. Osmotic shock of resting primary T cells in conjunction with anti-CD3 treatment was found to costimulate IL-2 production by the T cells, consistent with a pivotal role for JNK/SAPK in T cell costimulation.
Peptide Affinity and Concentration Affect the Sensitivity of M3-Restricted CTLs Induced In Vitro
Authors: Byers Derek E. , Lindahl Kirsten Fischer 
Published: December 2022

AbstractIn vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173–190, a peptide derived from influenza virus hemagglutinin (A/JAP/305/57, H2N2), induces CTLs that are directed to the MHC class Ib molecule, H2-M3. M3 preferably binds peptides bearing an N-terminal formylmethionine. In this study, we show that several related nonformylated peptides can induce anti-HA CTLs in vitro: MLIIW (the minimal epitope), derived from HA186–190 at the C-terminal end of HA173–190; MLIIWG; MLIIWGV; and MLIIWGI, as well as formylated MLIIW. The heptamer peptides correspond to a polymorphism of HA192 in H2 strains of influenza; they have the highest relative affinities for M3 of the nonformylated peptides and higher affinities than some formylated mitochondrial peptides. Depending on the affinity of the peptide, a range of concentrations can be used to induce CTLs. One nanomolar of the high affinity f-MLIIW peptide can induce anti-HA CTLs, whereas 100-fold more of the lower affinity MLIIW peptide is needed. Lines induced with high concentrations (1 μM or greater) of f-MLIIW recognize Ag poorly, and the most efficient CTLs are induced with the lowest concentrations of peptide. Analysis with a panel of anti-TCRVβ Abs shows that different T cells respond to high vs low peptide; the repertoire of cells responding to higher concentrations is more diverse, consistent with the expansion of more, but less efficient, clones. Thus, peptide affinity and concentration should be considered together for generating efficient antipeptide CTLs in vitro.
Human Rheumatoid Factor Production Is Dependent on CD40 Signaling and Autoantigen
Authors: Kyburz Diego , Corr Maripat , Brinson Diana C. , Von Damm Amila , Tighe Helen , Carson Dennis A. 
Published: December 2022

AbstractHigh-affinity pathologic rheumatoid factor (RF) B cells occur in autoimmune diseases such as rheumatoid arthritis, but are deleted in healthy individuals. The reasons for the survival and differentiation of these autoreactive B cells in rheumatoid arthritis are not known. Previous studies in mice transgenic for a human IgM RF have shown that peripheral encounter with soluble human IgG leads to deletion of high-affinity RF B cells; however, deletion can be prevented when concomitant T cell help is provided. This study aimed to further discern the minimal factors necessary not only for the in vivo survival of RF B cells, but also for their differentiation into Ab-secreting cells. The combination of MHC class II-reactive T cells and Ag induced the production of RF in human IgM RF transgenic mice, while either stimulus alone was ineffective. Neutralizing Abs against CD40 ligand (CD40L), but not against IL-4 or IL-15, abrogated IgM-RF production. Moreover, blockade of CD40L-CD40 allowed IgG to delete the RF precursor cells. Most importantly, activating Abs to CD40 could substitute entirely for T cell help in promoting the survival of RF precursors and in stimulating RF synthesis in T cell deficient animals. The data indicate that CD40 signaling alone can prevent deletion of RF B cells by Ag and in the presence of IgG is sufficient to trigger RF synthesis. The results suggest that selective induction of apoptosis in high-affinity RF B cells may be achieved by blockade of CD40L-CD40 interaction.
CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is Dispensable for CD8 T Cell Responses
Authors: Whitmire Jason K. , Flavell Richard A. , Grewal Iqbal S. , Larsen Christian P. , Pearson Thomas C. , Ahmed Rafi 
Published: December 2022

Abstract
This study documents a striking dichotomy between CD4 and CD8 T cells in terms of their requirements for CD40-CD40 ligand (CD40L) costimulation. CD40L-deficient (−/−) mice made potent virus-specific CD8 T cell responses to dominant as well as subdominant epitopes following infection with lymphocytic choriomeningitis virus. In contrast, in the very same mice, virus-specific CD4 T cell responses were severely compromised. There were 10-fold fewer virus-specific CD4 T cells in CD40L−/− mice compared with those in CD40L+/+ mice, and this inhibition was seen for both Th1 (IFN-γ, IL-2) and Th2 (IL-4) responses. An in vivo functional consequence of this Th cell defect was the inability of CD40L−/− mice to control a chronic lymphocytic choriomeningitis virus infection. This study highlights the importance of CD40-CD40L interactions in generating virus-specific CD4 T cell responses and in resolving chronic viral infection.
Selective Diapedesis of Th1 Cells Induced by Endothelial Cell RANTES
Authors: Kawai Toshihisa , Seki Makoto , Hiromatsu Kenji , Eastcott Jean W. , Watts Gerald F. M. , Sugai Motoyuki , Smith Daniel J. , Porcelli Steven A. , Taubman Martin A. 
Published: December 2022

AbstractDifferentiated CD4 T cells can be divided into Th1 and Th2 types based on the cytokines they produce. Differential expression of chemokine receptors on either the Th1-type or the Th2-type cell suggests that Th1-type and Th2-type cells differ not only in cytokine production but also in their migratory capacity. Stimulation of endothelial cells with IFN-γ selectively enhanced transmigration of Th1-type cells, but not Th2-type cells, in a transendothelial migration assay. Enhanced transmigration of Th1-type cells was dependent on the chemokine RANTES produced by endothelial cells, as indicated by the findings that Ab neutralizing RANTES, or Ab to its receptor CCR5, inhibited transmigration. Neutralizing Ab to chemokines macrophage-inflammatory protein-1α or monocyte chemotactic protein-1 did not inhibit Th1 selective migration. Whereas anti-CD18 and anti-CD54 blocked basal levels of Th1-type cell adherence to endothelial cells and also inhibited transmigration, anti-RANTES blocked only transmigration, indicating that RANTES appeared to induce transmigration of adherent T cells. RANTES seemed to promote diapedesis of adherent Th1-type cells by augmenting pseudopod formation in conjunction with actin rearrangement by a pathway that was sensitive to the phosphoinositol 3-kinase inhibitor wortmannin and to the Rho GTP-binding protein inhibitor, epidermal cell differentiation inhibitor. Thus, enhancement of Th1-type selective migration appeared to be responsible for the diapedesis induced by interaction between CCR5 on Th1-type cells and RANTES produced by endothelial cells. Further evidence that CCR5 and RANTES play a modulatory role in Th1-type selective migration derives from the abrogation of this migration by anti-RANTES and anti-CCR5 Abs.
The Mode of Ligand Recognition by Two Peptide:MHC Class I-Specific Monoclonal Antibodies
Authors: Messaoudi Ilhem , LeMaoult Joël , Nikolić-Z̆ugić Janko 
Published: December 2022

Abstract
The Ig superfamily members TCR and B cell receptor (BCR) share high structural and amino acid homology, yet interact with Ags in a distinct manner. The overall shape of the TCR ligand is rather constant, with the variation coming from the MHC polymorphism and the peptide heterogeneity. Consequently, the TCR α- and β-chains form a relatively flat ligand-binding site that interacts with the peptide:MHC (pep:MHC) ligand in a fixed diagonal orientation relative to the MHC α-helices, with the α- and β-chains of the TCR contacting the N and C termini of the pep:MHC complex, respectively. By contrast, the shape of BCR ligands varies dramatically, and the BCR exhibits much greater variability of the Ag-binding site. The mAbs 25-D1.16 (D1) and 22-C5.9 (C5), specific for the OVA-8:H-2Kb complex, allowed us to directly compare how TCR and BCR approach the same ligand. To that effect, we mapped D1 and C5 footprints over the OVA-8:H-2Kb complex. Using peptide variants and mutant MHC molecules, we show that the D1 and C5 contacts with the OVA-8:Kb complex C terminus overlap with the TCR β-chain footprint, but that this footprint also extends to the regions of the molecule not contacted by the TCR. These studies suggest that D1 and C5 exhibit a hybrid mode of pep:MHC recognition, in part similar to that of the TCR β-chain and in part similar to the conventional anti-MHC Ab.
Role of CD28 in the Generation of Effector and Memory Responses Required for Resistance toToxoplasma gondii
Authors: Villegas Eric N. , Elloso M. Merle , Reichmann Gaby , Peach Robert , Hunter Christopher A. 
Published: December 2022

AbstractCD28 deficient (CD28−/−) mice were used to study the role of costimulation in the T cell-mediated, IFN-γ-dependent mechanism of resistance to Toxoplasma gondii. These mice were resistant to infection with the ME49 strain of T. gondii. Analysis of the immune response of acutely infected CD28−/− mice revealed that IL-12 was required for T cell production of IFN-γ and this was independent of the CD40/CD40 ligand interaction. A similar mechanism of IL-12-dependent, CD28/B7 independent production of IFN-γ by T cells was also observed in wild-type mice. Interestingly, although chronically infected wild-type mice were resistant to rechallenge with the virulent RH strain of T. gondii, chronically infected CD28−/− mice were susceptible to rechallenge with the RH strain. This deficiency in the protective memory response by CD28−/− mice correlated with a lack of IL-2 and IFN-γ in recall responses and reduced numbers of CD4+ T cells expressing a memory phenotype. Together, our findings demonstrate that CD28 is not required for the development of a protective T cell response to T. gondii, but CD28 is required for an optimal secondary immune response.
Receptor-Mediated Modulation of Murine Mast Cell Function by α-Melanocyte Stimulating Hormone
Authors: Adachi Shiro , Nakano Teruaki , Vliagoftis Harrisios , Metcalfe Dean D. 
Published: December 2022

AbstractThe proopiomelanocortin (POMC)-derived neuropeptide α-melanocyte stimulating hormone (α-MSH) is known to modulate some aspects of inflammation through direct effects on T cells, B cells, and monocytes. To determine whether α-MSH might similarly influence mast cell responsiveness, mast cells were examined to see if they expressed the receptor for α-MSH, melanocortin-1 (MC-1), and whether α-MSH altered mast cell function. We thus first identified MC-1 on bone marrow cultured murine mast cells (BMCMC) and a murine mast cell line (MCP-5) employing flow cytometry and through detection of specific binding. Subsequent treatment of mast cells with α-MSH increased the cAMP concentration in a characteristic biphasic pattern, demonstrating that α-MSH could affect intracellular processes. We next examined the effect of α-MSH on mediator release and cytokine expression. IgE/DNP-human serum albumin-stimulated histamine release from mast cells was inhibited by ∼60% in the presence of α-MSH. Although activation of BMCMC induced the expression of mRNAs for the inflammatory cytokines IL-1β, IL-4, IL-6, TNF-α, and the chemokine lymphotactin, mRNAs for IL-1β, TNF-α, and lymphotactin were down-modulated in the presence of α-MSH. Finally, IL-3-dependent proliferative activity of BMCMC was slightly but significantly augmented by α-MSH. Taken together, these observations suggest that α-MSH may exert an inhibitory effect on the mast cell-dependent component of a specific inflammatory response.
Fc-Mediated Nonspecific Binding Between Fibronectin-Binding Protein I ofStreptococcus pyogenesand Human Immunoglobulins
Authors: Medina Eva , Molinari Gabriella , Rohde Manfred , Haase Bernd , Chhatwal Gursharan S. , Guzmán Carlos A. 
Published: December 2022

AbstractFibronectin-binding protein I (SfbI) from Streptococcus pyogenes plays a key role in bacterial adhesion to, and invasion of, eukaryotic cells. In addition, SfbI exhibits a considerable potential as mucosal adjuvant and can trigger polyclonal activation of B cells. Here, we report that SfbI is also capable of binding human IgG in a nonimmune fashion. SfbI was reactive with IgG1, IgG2, IgG3, and IgG4 isotypes (type IIo IgG-binding profile). The affinity constant (Kd) of the SfbI-IgG interaction was in the range of 1–2 × 10−5 M. Further studies demonstrated that the SfbI binding was mediated by the Fc component of the IgG molecule. Experiments performed using purified recombinant proteins spanning different domains of SfbI showed that the IgG-binding activity was restricted to the fibronectin-binding domains, and in particular to the fibronectin-binding repeats. Finally, the presence of recombinant SfbI resulted in an impairment of both phagocytosis of IgG-coated RBCs and Ab-dependent cell cytotoxicity by macrophages. These results demonstrated for the first time that, in addition to its major role during the colonization process, SfbI may also favor bacterial immune evasion after the onset of the infection by interfering with host clearance mechanisms.
Molecular Mechanisms Underlying IL-4-Induced Leukocyte Recruitment In Vivo: A Critical Role for the α4 Integrin
Authors: Hickey Michael J. , Granger D. Neil , Kubes Paul 
Published: December 2022

AbstractIL-4 is known to induce recruitment of eosinophils and mononuclear leukocytes. In vitro this occurs in part by selective expression of VCAM-1, the ligand for the α4 integrin. The objective of this study was to determine the molecular mechanisms that underlie IL-4-induced leukocyte recruitment in vivo. Mice received an intrascrotal injection of IL-4 (100 ng). Twenty-four hours later, leukocyte rolling, adhesion, and emigration in cremasteric postcapillary venules were examined via intravital microscopy, and expression of VCAM-1 and P- and E-selectin was quantitated using a radiolabeled mAb technique. IL-4 increased VCAM-1 expression, but P-selectin and E-selectin remained at constitutive levels. IL-4 induced significant increases in leukocyte adhesion and emigration, with 50% of the emigrated cells being eosinophils and the remainder being mononuclear leukocytes. Leukocyte rolling in IL-4-treated mice was &gt;95% inhibitable using an anti-P-selectin Ab. However, IL-4-induced leukocyte recruitment was unaltered in mice treated chronically with P-selectin Ab or mice deficient in either P-selectin or P- and E-selectin, suggesting that the residual rolling supported all of the IL-4-induced recruitment. In IL-4-treated mice following P-selectin blockade, tethering and rolling were not dependent on L-selectin, but were abolished by α4 integrin blockade. These findings show that the α4 integrin can initiate leukocyte-endothelial cell interactions in the absence of selectins under shear conditions in vivo, and that the absence of selectins does not affect recruitment of eosinophils and mononuclear cells to IL-4-treated tissue.
Markers of Lymphocyte Homing Distinguish CD4 T Cell Subsets That Turn Over in Response to HIV-1 Infection in Humans
Authors: Hengel Richard L. , Jones Bonnie M. , Kennedy M. Susan , Hubbard Marjorie R. , McDougal J. Steven 
Published: December 2022

AbstractIn HIV-1 infection, the abrupt rise in CD4 T cells after effective antiretroviral therapy has been viewed as a measure of HIV-1-related CD4 T cell turnover in the steady state. The early (2–4 wk) response is reportedly dominated by CD4 T cells with a memory (CD45RO) phenotype. It is controversial whether the measurement of steady-state kinetics identifies cells that otherwise would have been recruited into a short-lived, virus-producing pool or reflects lymphoid redistribution/sequestration. We performed detailed phenotypic and kinetic analysis of CD4 T cell subsets in 14 patients. Turnover occurs in memory (CD45RO) as well as naive (CD45RA) cells, if the latter are present at baseline. Most of the turnover occurs in those memory (CD45RO) and naive (CD45RA) cells that are programmed for recirculation through lymphoid organs (CD62L+ and CD44low), whereas very little turnover occurs in memory cells (CD45RO) destined for recirculation from blood to tissue (CD62L− and CD44high). Turnover occurs in both activated (CD25+ and HLA-DR+) and nonactivated populations, although it is restricted to CD38-positive cells, indicating that turnover does not measure cells that are already infected. More likely, turnover occurs in cells that replace infected cells or are on their way to becoming infected. Taken together, markers of lymphocyte trafficking better describe cell turnover related to virus replication than do naive and memory markers per se, and lymph organs, not tissue-destined cells or peripheral blood cells, appear to be the important site of virus replication and CD4 T cell turnover, destruction, and redistribution.
Cutting Edge: Paradigm Revisited: Antibody Provides Resistance toListeriaInfection
Authors: Edelson Brian T. , Cossart Pascale , Unanue Emil R. 
Published: December 2022

AbstractListeriolysin O (LLO) is a secreted pore-forming toxin of the facultative intracellular bacterium Listeria monocytogenes. We assessed the ability of a murine anti-LLO mAb to affect the course of infection in mice challenged with Listeria. This mAb was previously shown to be capable of neutralizing LLO-mediated pore formation in vitro, and here we show that the passive administration of this Ab to mice before infection provides increased resistance. Mice treated with the mAb were protected from a lethal challenge with virulent Listeria and showed a significant reduction in Listeria burden during the first hours to days postinfection. These effects of the Ab were independent of host B or T cells, since treatment with the mAb provided enhanced resistance to SCID mice. The titer of anti-LLO Abs during the regular infection of mice with Listeria was found to be low to negative.