bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nasal Immunization of Nonhuman Primates with Simian Immunodeficiency Virus p55gagand Cholera Toxin Adjuvant Induces Th1/Th2 Help for Virus-Specific Immune Responses in Reproductive Tissues
Authors: Imaoka Koichi , Miller Christopher J. , Kubota Mitsuru , McChesney Michael B. , Lohman Barbara , Yamamoto Masafumi , Fujihashi Kohtaro , Someya Kenji , Honda Mitsuo , McGhee Jerry R. , Kiyono Hiroshi 
Published: January 2023

AbstractFemale rhesus macaques were nasally immunized with p55gag (p55) of SIV and cholera toxin as a mucosal adjuvant. Nasal immunization induced Ag-specific IgA and IgG Abs in mucosal secretions (e.g., cervicovaginal secretions, rectal washes, and saliva) and serum. Furthermore, high numbers of p55-specific IgA and IgG Ab-forming cells were induced in mucosal effector sites, i.e., uterine cervix, intestinal lamina propria, and nasal passage. p55-specific CD4+ T cells in both systemic and mucosal compartments expressed IFN-γ and IL-2 (Th1-type)- as well as IL-5, IL-6, and IL-10 (Th2-type)-specific mRNA. Moreover, p55-specific CTL activity was demonstrated in lymphocytes from blood, tonsils, and other lymphoid tissues. These results show that nasal immunization with SIV p55 with cholera toxin elicits both Th1- and selective Th2-type cytokine responses associated with the induction of SIV-specific mucosal and serum Abs, and CTL activity. These results offer a promise for the development of protective mucosal immunity to SIV.
Signaling Pathways Mediated by the TNF- and Cytokine-Receptor Families Target a Commoncis-Element of the IFN Regulatory Factor 1 Promoter
Authors: Gupta Sanjay , Xia Dengfeng , Jiang Man , Lee Sangjin , Pernis Alessandra B. 
Published: January 2023

AbstractCD40 activation of B cells is strongly influenced by the presence of cytokines. However, the molecular basis for the interplay between these distinct stimuli is not clearly delineated. IFN regulatory factor 1 (IRF-1) is a transcription factor activated by either CD40 or cytokines. We have found that these different sets of signals target a common cis-acting element in the promoter of this gene, the IRF-1 gamma-activated site (GAS). Targeting of the IRF-1 GAS is not confined to activation via CD40 but extends to other stimuli that mimic the CD40 signaling cascade, like TNF-α and EBV. In contrast to induction of STATs by cytokines, the IRF-1 GAS-binding complex activated by CD40, TNF-α, or EBV contains Rel proteins, specifically p50 and p65. In this system, simultaneous exposure to CD40L together with either IL-4 or IFN-γ does not lead to the activation of novel Rel/STAT complexes. Given the importance of IRF-1 in a variety of biologic functions from proliferation to apoptosis, our findings support the notion that modulation of IRF-1 levels may be a critical control point in B cell activation.
Human CD5 Signaling and Constitutive Phosphorylation of C-Terminal Serine Residues by Casein Kinase II
Authors: Calvo Javier , Vildà Josep M. , Places Lourdes , Simarro María , Padilla Olga , Andreu David , Campbell Kerry S. , Aussel Claude , Lozano Francisco 
Published: January 2023

AbstractCD5 is a lymphocyte surface glycoprotein with a long cytoplasmic domain suitable for phosphorylation and signal transduction, which is involved in the modulation of Ag-specific receptor-mediated activation and differentiation signals. In this study, we use Jurkat T cell transfectants of CD5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase II (CKII) is responsible for the constitutive phosphorylation of CD5 molecules at a cluster of three serine residues located at the extreme C terminus (S458, S459, and S461). Furthermore, the yeast two-hybrid system demonstrates the specific association between the C-terminal regions of the CD5 cytoplasmic tail and the regulatory β subunit of CKII. We demonstrate that CKII associates with and phosphorylates the C-terminal region of CD5, a conserved domain known to be relevant for the generation of second lipid messengers, and thereby enables at least one component of its signaling funcion.
Regulation of the Activity of IFN-γ Promoter Elements During Th Cell Differentiation
Authors: Zhang Feng , Wang Ding Zhe , Boothby Mark , Penix Laurie , Flavell Richard A. , Aune Thomas M. 
Published: January 2023

AbstractBefore they can deliver their effector functions, CD4+ Th cells must differentiate into Th1 or Th2 subsets. We have prepared reporter transgenic mice that express the luciferase gene under the control of proximal (prox.IFN-γ) and distal (dist.IFN-γ) regulatory elements from the IFN-γ promoter to permit investigation of mechanisms that regulate IFN-γ gene transcription during Th cell differentiation. Precursor Th cells (pTh) contain high levels of cAMP response element binding protein-activation transcription factor-1 (CREB-ATF1) proteins that bind these promoter elements from the IFN-γ gene, and these cells fail to express promoter activity. Restimulated effector Th (eTh) cells have reduced levels of CREB-ATF1 proteins, their nuclear extracts exhibit reduced CREB-ATF1 binding and greater Jun and Jun-ATF2 binding to dist.IFN-γ, and eTh cells express promoter activity. CREB directly competes with effector T cell nuclear proteins for dist.IFN-γ binding, and overexpression of CREB inhibits both prox.IFN-γ- and dist.IFN-γ-directed transcription in Jurkat T cells. IL-12-stimulated Th1 differentiation increases dist.IFN-γ activity in restimulated eTh1 cells; eTh1 nuclear extracts form increased levels of Jun-ATF2-dist.IFN-γ complexes. Taken together, these data suggest that both de-repression and trans-activation contribute to the induction of IFN-γ gene transcription during Th1 differentiation.
CD36 Is Required for Phagocytosis of Apoptotic Cells by Human Macrophages That Use Either a Phosphatidylserine Receptor or the Vitronectin Receptor (αvβ3)
Authors: Fadok Valerie A. , Warner Mary L. , Bratton Donna L. , Henson Peter M. 
Published: January 2023

AbstractIn vivo, apoptotic cells are efficiently removed by professional or nonprofessional phagocytes, a process thought to be essential for tissue remodeling and resolution of inflammation. Macrophages recognize apoptotic cells by several mechanisms, including recognition of exposed phosphatidylserine (PS); however, PS recognition on apoptotic cells has not been identified as a feature of human macrophages. The purpose of this study was to determine whether human monocyte-derived macrophages could be stimulated to recognize PS, defined as inhibition of phagocytosis by PS-containing liposomes. We also assessed the potential roles for scavenger receptors, CD14, and lectins. Uptake of apoptotic neutrophils into unstimulated macrophages was blocked about 50% by Arg-Gly-Asp-Ser and anti-αv, and up to 20% by oxidized low density lipoprotein and N-acetylglucosamine, implying a major role for integrin and minor roles for scavenger and lectin receptors. Uptake into macrophages stimulated with β-1,3-glucan was blocked 50% by PS liposomes and 40% by oxidized low density lipoprotein, suggesting that the macrophages had switched from using integrin to recognition of PS. MEM-18 and 61D3 (anti-CD14 mAbs) were poor inhibitors of apoptotic neutrophil uptake, but good inhibitors of apoptotic lymphocyte uptake. The switch to PS recognition was accompanied by down-regulation of αvβ3 expression and function. Anti-CD36 blocked uptake into unstimulated or stimulated macrophages, suggesting CD36 involvement not only with the αvβ3 integrin mechanism (as previously reported) but also with PS recognition. A maximum of 70% inhibition was achieved by combining anti-CD36 with either anti-av or PS liposomes.
Blood Monocyte Migration to Acute Lung Inflammation Involves Both CD11/CD18 and Very Late Activation Antigen-4-Dependent and Independent Pathways
Authors: Li Xian Chang , Miyasaka Masayuki , Issekutz Thomas B. 
Published: January 2023

AbstractIn acute lung inflammation, blood neutrophils and monocytes migrate into the lung parenchyma and bronchoalveolar space. The infiltration of the inflamed lung by monocytes is poorly understood because of difficulties in quantifying these cells in the presence of resident macrophages. Radiolabeled monocytes were used to study monocyte migration into the inflamed rat lung. Monocytes and neutrophils were purified from blood, labeled with 51Cr and 111In, respectively, and injected i.v. into rats given an intratracheal injection of LPS. The accumulation of 51Cr-labeled monocytes increased &gt;10-fold in the lung parenchyma and 170-fold in the bronchoalveolar lavage (BAL) 18 h after LPS. 111In-labeled neutrophils increased &gt;30-fold in the lung tissue and 500-fold in the BAL. Treatment of rats with a blocking anti-CD18 mAb inhibited monocyte accumulation in the lung and BAL by about 30%, whereas blocking very late activation Ag-4 (VLA-4) had no effect. Combined blockade of VLA-4 and CD18 inhibited approximately 30% of the migration to the lung parenchyma, but decreased the BAL by 80%. Monocyte migration to cutaneous inflammation was completely abolished by the combined mAb treatment. Neutrophil accumulation in the lung and BAL was not decreased by blocking either CD18 or VLA-4 and was only partially reduced by blocking CD18 plus VLA-4. Thus, monocyte migration to the LPS inflamed lung is substantially CD11/CD18 and VLA-4 independent, but accumulation in BAL is mediated by CD18 and VLA-4. Monocytes as well as neutrophils may use a previously unrecognized endothelial adhesion and migration pathway in the lung.
Engagement of ICAM-3 Activates Polymorphonuclear Leukocytes: Aggregation Without Degranulation or β2 Integrin Recruitment
Authors: Feldhaus Michael J. , Kessel Julie M. , Zimmerman Guy A. , McIntyre Thomas M. 
Published: January 2023

AbstractICAM-3 is a preferred counterreceptor for the leukocyte αLβ2 integrin. It activates T cells through outside-in signaling, but polymorphonuclear leukocytes (PMN) are reported to be refractory to ICAM-3 stimulation. We found that engagement of ICAM-3 by a mAb (CAL3.10), which binds in the region where αLβ2 integrin binds, activates PMN homotypic aggregation and adhesion to surfaces. These functional changes were due to ICAM-3 outside-in signaling because aggregation and adhesion were β2 integrin-dependent, tyrosine kinase and protein kinase C activities were activated, and there was a reorganization of the cytoskeleton. This reorganization and kinase activity was required for ICAM-3-, but not FMLP-, induced aggregation. This is not an Fc-mediated event as an appropriate anti-ICAM-3 F(ab′)2 fragment still induced aggregation. Another anti-ICAM-3 Ab (HP2/19), which activates T cells, did not activate PMN. Strikingly, anti-ICAM-3 did not induce degranulation or cause an increase in surface β2 integrin expression, so adhesion and aggregation were due solely to the activation of the constitutively expressed β2 integrins. Aggregation in response to ICAM-3, but not FMLP, was compromised at lower cell densities, showing that β2 integrin recruitment enhances aggregation under suboptimal conditions. We conclude that engagement of ICAM-3 stimulates PMN as well as T cells, but that the appropriate epitope varies between these two cells. ICAM-3 outside-in signaling reorganizes the cytoskeleton without causing degranulation, induces serine and tyrosine kinase activation, and activates existing surface β2 integrins to a proadhesive state.
Oral Delivery of Group A Streptococcal Cell Walls Augments Circulating TGF-β and Suppresses Streptococcal Cell Wall Arthritis
Authors: Chen Wanjun , Jin Wenwen , Cook Melissa , Weiner Howard L. , Wahl Sharon M. 
Published: January 2023

AbstractOral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 μg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 μg), but not intermediate (30 μg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10–15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-β was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-β, concomitant with decreased circulating TNF-α and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-β dependent. These data support a pivotal role for TGF-β, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.
Substance P Regulates Somatostatin Expression in Inflammation
Authors: Blum Arthur M. , Elliott David E. , Metwali Ahmed , Li Jie , Qadir Khurram , Weinstock Joel V. 
Published: January 2023

AbstractSubstance P (SP) and somatostatin (SOM) are made at mucosal surfaces and sites of inflammation. There is a SP/SOM immunoregulatory circuit that modulates the IFN-γ response in murine schistosomiasis. SP enhances, while SOM decreases, IFN-γ secretion. Various inflammatory mediators induce macrophages to make SOM, but no known factor limits this expression. It was discovered that SP regulates SOM synthesis. Splenocytes from normal, uninfected mice cultured with LPS, IFN-γ, or IL-10 for 4 h strongly expressed SOM mRNA, but failed to do so in the presence of SP. The inhibition with 10−9 M SP was &gt;85% shown by quantitative PCR. Also, splenocyte SOM content decreased from 1048 ± 275 to &lt;10 pg/4 × 108 cells following SP exposure. Immunohistochemistry identified SOM solely within splenic macrophages following cytokine stimulation. Mice infected with Schistosoma mansoni form granulomas in the liver and intestines resulting from deposition of parasite eggs in these organs. The granulomas contain macrophages that make SOM constitutively. SP at 10−8 M decreased SOM mRNA expression &gt;90% in dispersed granuloma cells cultured for 4 h or longer. Specific SP receptor antagonists blocked SP suppression of SOM expression in splenocytes and dispersed granuloma cells, showing that an authentic SP receptor mediated the regulation. Additional studies revealed that IL-4 antagonized the SP effect in the spleen. It is concluded that in granulomas and splenocytes from mice with schistosomiasis and in splenocytes from uninfected animals that 1) SP inhibits macrophage SOM induction and ongoing expression at the mRNA and protein levels acting through the SP receptor, and 2) IL-4 can antagonizes this SP effect.
CDw150 Associates with Src-Homology 2-Containing Inositol Phosphatase and Modulates CD95-Mediated Apoptosis
Authors: Mikhalap Svitlana V. , Shlapatska Larisa M. , Berdova Anna G. , Law Che-Leung , Clark Edward A. , Sidorenko Svetlana P. 
Published: January 2023

Abstract
CDw150, a receptor up-regulated on activated T or B lymphocytes, has a key role in regulating B cell proliferation. Patients with X-linked lymphoproliferative disease have mutations in a gene encoding a protein, DSHP/SAP, which interacts with CDw150 and is expressed in B cells. Here we show that CDw150 on B cells associates with two tyrosine-phosphorylated proteins, 59 kDa and 145 kDa in size. The 59-kDa protein was identified as the Src-family kinase Fgr. The 145-kDa protein is the inositol polyphosphate 5′-phosphatase, SH2-containing inositol phosphatase (SHIP). Both Fgr and SHIP interact with phosphorylated tyrosines in CDw150’s cytoplasmic tail. Ligation of CDw150 induces the rapid dephosphorylation of both SHIP and CDw150 as well as the association of Lyn and Fgr with SHIP. CD95/Fas-mediated apoptosis is enhanced by signaling via CDw150, and CDw150 ligation can override CD40-induced rescue of CD95-mediated cell death. The ability of CDw150 to regulate cell death does not correlate with serine phosphorylation of the Akt kinase, but does correlate with SHIP tyrosine dephosphorylation. Thus, the CDw150 receptor may function to regulate the fate of activated B cells via SHIP as well as via the DSHP/SAP protein defective in X-linked lymphoproliferative disease patients.
Tumor Antigens are Constitutively Presented in the Draining Lymph Nodes
Authors: Marzo Amanda L. , Lake Richard A. , Lo David , Sherman Linda , McWilliam Andrew , Nelson Delia , Robinson Bruce W. S. , Scott Bernadette 
Published: January 2023

Abstract
Tumor growth is rarely associated with a strong specific CTL response, suggesting that the immune system is ignorant of the presence of tumor because the Ags are not readily available to or are sequestered from potential effector cells. We studied the in vivo activation of naive TCR transgenic hemagglutinin (HA)-specific CD8+ T cells adoptively transferred into mice bearing HA-expressing tumor using 5,6-carboxy-succinimidyl-fluorescein-ester labeling, which allows the identification of proliferating HA-specific T cells. We demonstrate that tumor Ags are constitutively presented in the lymph nodes draining tumors and are powerfully mitogenic for responding T cells despite the absence of anti-tumor CTL responses. Importantly, this proliferative signal occurs throughout tumor growth and is still detectable 6 mo after tumor inoculation when tumor is not palpable. These results provide the first evidence that there is constitutive presentation of tumor Ags in draining lymph nodes.
Pertussis Toxin-Sensitive Signal Controls the Trafficking of Thymocytes Across the Corticomedullary Junction in the Thymus
Authors: Suzuki Gen , Sawa Hirofumi , Kobayashi Yoshiyasu , Nakata Yukiko , Nakagawa Ken-ichi , Uzawa Akiko , Sakiyama Hisako , Kakinuma Shizuko , Iwabuchi Kazuya , Nagashima Kazuo 
Published: January 2023

Abstract
We investigated a role of chemokines in thymocyte trafficking. Genes encoding stromal cell-derived factor-1 and its receptor CXCR4 were detected in the cortex by in situ hybridization. Early immigrant cells did not express CXCR4, whereas their descendant CD44+CD25+CD4−CD8− cells did. CXCR4 expression was down-modulated when CD4+CD8+ double-positive cells became CD4+CD8− or CD4−CD8+ single-positive (SP) cells. Positively selected CD69+CD3intermediate cells gained CCR4, of which ligand, thymus activation-regulated chemokine, was expressed in the medulla. At the next developmental stage, CD69−CD3high cells lost CCR4 but gained CCR7. These results suggest that thymocytes use different chemokines along with their development. Blockade of chemokine receptor-mediated signaling by pertussis toxin perturbed the normal distribution of SP cells and resulted in the accumulation of SP cells in the cortex. Thus, a pertussis toxin-sensitive event controls the trafficking of SP cells across the corticomedullary junction.
CD8+ CTLs Are Essential for Protective Immunity Against Encephalitozoon cuniculi Infection
Authors: Khan Imtiaz A. , Schwartzman Joseph D. , Kasper Lloyd H. , Moretto Magali 
Published: January 2023

Abstract
Encephalitozoon cuniculi is a protozoan parasite that has been implicated recently as a cause of opportunistic infection in immunocompromised individuals. Protective immunity in the normal host is T cell-dependent. In the present study, the role of individual T cell subtypes in immunity against this parasite has been studied using gene knockout mice. Whereas CD4−/− animals resolved the infection, mice lacking CD8+ T cells or perforin gene succumbed to parasite challenge. The data obtained in these studies suggest that E. cuniculi infection induces a strong and early CD8+ T response that is important for host protection. The CD8+ T cell-mediated protection depends upon the CTL activity of this cell subset, as the host is rendered susceptible to infection in the absence of this function. This is the first report in which a strong dependence upon the cytolytic activity of host CD8+ T cells has been shown to be important in a parasite infection.
The Surface Protein Superfamily ofTrypanosoma cruziStimulates a Polarized Th1 Response That Becomes Anergic
Authors: Millar Amanda E. , Wleklinski-Lee Monika , Kahn Stuart J. 
Published: January 2023

AbstractTrypanosoma cruzi is an obligate intracellular parasite that chronically infects mammals. Extracellular mammalian stage trypomastigotes simultaneously express and release multiple members of the parasite’s surface protein superfamily; these extracellular proteins should stimulate MHC class II-restricted CD4 T cells. The surface protein superfamily, however, encodes variant epitopes that may inhibit this CD4 response. In this report the surface protein-specific CD4 response was investigated. CD4 cells isolated from acutely and chronically infected mice did not proliferate when stimulated with surface proteins. Adoptive transfer of surface protein-specific CD4 clones or immunization with a peptide encoding a surface protein T cell epitope protected mice during T. cruzi infection. These data strongly suggested that surface proteins were expressed and presented to CD4 cells during infection. Limiting dilution analysis identified an expanded population of surface protein-specific CD4 cells during the acute and chronic infection. These surface protein-specific CD4 cells did not produce IL-2 or IL-4, but did produce IFN-γ. Enzyme-linked immunospot analyses confirmed that many of the surface protein-specific CD4 cells produce IFN-γ. Together these results suggest that during T. cruzi infection a potentially protective CD4 response becomes anergic. It is possible that this anergy is induced by variant T cell epitopes encoded by the surface protein superfamily.
TNF-Induced Haptoglobin Release from Human Neutrophils: Pivotal Role of the TNF p55 Receptor
Authors: Berkova Nadia , Gilbert Caroline , Goupil Serge , Yan Ju , Korobko Vyatcheslav , Naccache Paul H. 
Published: January 2023

AbstractHaptoglobin (Hp), TNF-α, and neutrophils are parts of a highly interactive ensemble participating in inflammatory processes. Hp is taken up by neutrophils, stored within a cytoplasmic granular compartment, and is secreted during phagocytosis by those cells. In the present study, the effects of TNF-α on the release of Hp from human neutrophils were investigated. Incubation of neutrophils with TNF-α induced the release of Hp from cells in a time- and concentration-dependent manner as revealed by Western blot analysis and immunofluorescence. The release of Hp induced by TNF-α was not due to nonspecific lysis of the cells. TNF-α is a highly pleiotropic cytokine that mediates its effects by binding to two distinct receptors (p55 and p75). Administration of TNF-α mutants binding specifically either to the p55 or to the p75 TNF receptors showed that there is a preference of TNF-α for the p55 receptor in the mediation of Hp release by neutrophils. A stimulated release of Hp was also induced by the chemotactic tripeptide fMLP. The TNF-α-induced release of Hp from neutrophils was inhibited by erbstatin, a tyrosine kinase inhibitor. These findings suggest that TNF-α may promptly increase the level of Hp at sites of infection or injury, leading to the modulation of the acute inflammatory response.