bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of competence to respond to IL-4 by CD4+ T helper type 1 cells requires costimulation.
Authors: Chiodetti L , Schwartz R H 
Published: December 2022

Abstract
Rested murine CD4+ Th1 clones do not produce IL-4, but have previously been shown to be capable of responding to IL-4 if they are first activated with Ag and APC. In this study, we have examined the activation requirements for induction of competence to respond to IL-4 in these clones. TCR occupancy alone (given either as chemically fixed APC and Ag, anti-CD3, Con A, or ionomycin and PMA) was inadequate, but the addition of a source of costimulation to any of these stimuli resulted in complete induction of competence to respond to IL-4. Pretreatment of the Th1 clones with TCR occupancy alone induced an anergic state from which subsequent full stimulation with Ag and APC failed to give IL-4 responsiveness. Pretreatment of the cells with IL-2 alone was an inadequate signal to induce IL-4 responsiveness and only a partial response was obtained when TCR occupancy was combined with IL-2. Addition of anti-IL-2 and anti-IL-2R antibodies during full activation with APC and Ag gave a 50% inhibition of competence induction. These results demonstrate that costimulation, in addition to its role in IL-2 production, is an important second signal for inducing T cells to become competent to respond to IL-4.
Influence of resistant and susceptible genotype, IL-1, and lymphoid organ on Trichinella spiralis-induced cytokine secretion.
Authors: Pond L , Wassom D L , Hayes C E 
Published: December 2022

Abstract
The relative importance of cell-mediated inflammatory responses and antibody-mediated responses in controlling parasitic helminth infection is debated. To study the relationship between these responses and resistance or susceptibility to primary Trichinella spiralis infection, we infected resistant AKR mice and susceptible B10.BR mice and analyzed the lymphokines IL-2, IFN-gamma, and IL-5 produced by their T cells as a function of time and lymphoid organ. IL-2-secretors occurred maximally between days 3 and 6 postinfection, whereas IL-5-secretors peaked between days 6 and 9. Previously, we found that IFN-gamma producers peaked before day 6, whereas IL-4 producers peaked between days 6 and 9. Most cytokine secretors were CD4+. The simultaneous development of IL-2- and IFN-gamma-secreting cells, and IL-4- and IL-5-secreting cells, suggests that the infection may be stimulating T cells to differentiate into cells capable of secreting specific cytokine sets, analogous to the postulated Th1 and Th2 subsets. In the spleen and mesenteric lymph nodes, cells from B10.BR mice secreted more IL-5 than cells from AKR mice, as we found previously for IL-4. For both strains, mesenteric lymph node cells produced more IL-5 than splenocytes. The AKR mesenteric lymph node cells produced more IL-2 than the B10.BR cells, but the reverse occurred in splenocytes. The AKR peripheral lymph node cells also secreted more IFN-gamma than the B10.BR cells, but the strains were equivalent for peritoneal exudate cell IFN-gamma production. Thus, the lymphoid organ microenvironment plays an important role in regulating cytokine-secreting cell development in this system. We also tested the possible regulatory role of IL-1. Exogenous rIL-1 alpha increased IFN-gamma secretion early but not late in mesenteric lymph node cells from both strains; this reflected an increased IFN-gamma-secreting cell frequency, not a change in IFN-gamma mRNA transcript level. Exogenous rIL-1 alpha did not consistently affect IL-2, IL-4, or IL-5 secretion. These data suggest that IL-1 alpha availability in vivo may regulate IFN-gamma-secreting cell development. In sum, early activation of IFN-gamma-secreting T cells in lymph nodes, with little subsequent activation of IL-4- and IL-5-secreting cells, distinguished the resistant from susceptible strain responses to T. spiralis infection, and IL-1 alpha and lymphoid organ environment influence IFN-gamma-secreting cell activation.
Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein.
Authors: Sedegah M , Sim B K , Mason C , Nutman T , Malik A , Roberts C , Johnson A , Ochola J , Koech D , Were B 
Published: December 2022

Abstract
In rodent malaria model systems, protective immunity induced by immunization with irradiated sporozoites is eliminated by in vivo depletion of CD8+ T cells, and adoptive transfer of CTL clones against the circumsporozoite protein protects against malaria. We recently demonstrated that volunteers immunized with irradiated Plasmodium falciparum sporozoites produce CTL against peptide 368-390 of the P. falciparum circumsporozoite protein. To determine whether natural exposure to malaria induced similar CTL, we studied 11 adult, male, life-long residents of a highly malarious area of Kenya, who were selected because their lymphocytes had been shown to proliferate after stimulation with peptides 361-380, 371-390, or 368-390 and because nine had been resistant to malaria in previous studies. In four of the 11 individuals there was peptide-specific, genetically restricted, CTL activity. In all four individuals, this activity was unaffected by depletion of CD4+ T cells. In three volunteers the activity was eliminated or reduced by depletion of CD8+ T cells; in the fourth volunteer the CD8+ T cell depletion was uninterpretable. This first demonstration of CD8+ T cell, genetically restricted, Ag-specific CTL against a malaria protein among individuals exposed to endemic malaria provides a foundation for studying the relationship between circulating CTL and resistance to malaria infection.
Cross-protection against influenza virus infection afforded by trivalent inactivated vaccines inoculated intranasally with cholera toxin B subunit.
Authors: Tamura S , Ito Y , Asanuma H , Hirabayashi Y , Suzuki Y , Nagamine T , Aizawa C , Kurata T 
Published: December 2022

Abstract
Cross-protection against influenza virus infection was examined in mice, immunized intranasally with a nasal site-restricted volume of inactivated vaccines together with cholera toxin B subunit (CTB) as an adjuvant. The mice were challenged with either a small or a large volume of mouse-adapted virus suspension, each of which gave virgin mice either a predominant upper or lower respiratory tract infection. A single dose of a monovalent influenza A H3N2 virus vaccine with CTB provided complete cross-protection against the small-volume challenge with a drift virus within the same subtype, but a slight cross-protection against the large-volume challenge. A second dose of another drift virus vaccine increased the efficacy of cross-protection against the large-volume challenge. Similar cross-protection against H1N1, H3N2, or B type drift virus challenge was provided in the mice having received a primary dose of a mixture of H1N1, H3N2, and B virus vaccines with CTB and a second dose of another trivalent vaccine. The degree of cross-protection against the small- and the large-volume infection paralleled mainly the amount of cross-reacting IgA antibodies to challenge virus hemagglutinin in the nasal wash and that of cross-reacting IgG antibodies in the bronchoalveolar wash, respectively. On the other hand, in mice immunized subcutaneously with the trivalent vaccines having no cross-reacting IgA antibodies, the efficacy of cross-protection was not so high as that of nasal vaccination. These results suggest that the nasal inoculation of trivalent vaccines with CTB provides cross-protection against a broader range of viruses than does the current parenteral vaccination.
Cross-linking of sialophorin (CD43) induces neutrophil aggregation in a CD18-dependent and a CD18-independent way.
Authors: Kuijpers T W , Hoogerwerf M , Kuijpers K C , Schwartz B R , Harlan J M 
Published: December 2022

Abstract
Normal human neutrophils bound an as yet unclustered mAb designated BS-1. The Ag immunoprecipitated with BS-1 was blotted by CD43 mAb (and vice versa), and is therefore identical to the large sialoglycoprotein. The CD43 Ag expression on the neutrophil surface is decreased upon neutrophil activation with the chemoattractant FMLP or with PMA. This can be (at least partially) explained by the release of CD43+ material with an altered electrophoretic mobility into the extracellular medium of the neutrophils upon activation. Cross-linking of the CD43 Ag with BS-1 also invoked neutrophil activation by itself: F(ab)2 fragments of BS-1-induced neutrophil aggregation, in contrast to F(ab) fragments. Neither respiratory burst activity nor a significant rise in intracellular Ca2+ level or actin polymerization were observed. The transient neutrophil aggregation response was largely CD18 dependent, especially in the initial phase of homotypic clustering. However, a significant CD18-independent mechanism contributed thereafter to the neutrophil aggregation, as was further substantiated by the use of cultured T (and EBV-transformed B) cell clones of a patient with a leukocyte adhesion deficiency. CD43 is the first molecule described on neutrophils able to induce adhesive properties in a dual fashion.
Receptor-mediated activation of human B lymphocytes in a nonphosphotyrosine-dependent manner.
Authors: Roifman C M , Wang G 
Published: December 2022

Abstract
The B cell AgR regulates two signal transduction pathways: the tyrosine kinase and the phosphatidylinositol (PtdIns) pathways. Stimulation of B cells with Ag or anti-Ig antibody results in a rapid increase in tyrosine phosphorylation of multiple substrates. The AgR also mediates the activation of phospholipase C-gamma 1 (PLC-gamma 1) thus producing the second messengers, inositol trisphosphate and diacylglycerol. Although the detailed relationship between these two signaling pathways remains unclear, it has recently become apparent that PLC-gamma 1 might be a target for the AgR-associated protein tyrosine kinase. To address the question of whether tyrosine kinase activity is essential for B cell activation, we studied early biochemical changes and later cellular events induced by ligation of the purinoceptor (P2R). Ligation of ATP to its receptor on B cells has been previously shown to elicit increases in cytosolic free Ca2+ and inositol phosphate production as well as induction of c-fos mRNA expression and increased expression of IL-2 and transferrin receptors. We show here that ATP in a wide range of concentrations did not increase protein tyrosine kinase activity. In contrast with the AgR, P2R did not mediate tyrosine phosphorylation of PLC-gamma 1, thus suggesting that it may use another phosphoinositide-specific PLC that does not require phosphorylation on tyrosine residues for its activation. The results were supported by experiments with a specific tyrosine kinase inhibitor, tyrphostin AG-126. Preincubation with this inhibitor blocked AgR but not P2R-mediated inositol phosphate production, cytosolic free Ca2+ changes, and IL-2 and transferrin receptor expression. The results indicate that the PtdIns pathway may be sufficient to induce activation of B cells and that the tyrosine phosphorylation pathway is not necessary for nonantigenic B cell activation.
Mice deprived of exogenous antigenic stimulation develop a normal repertoire of functional T cells.
Authors: Vos Q , Jones L A , Kruisbeek A M 
Published: December 2022

Abstract
The development of T cells and the selection of the TCR repertoire in the absence of exogenous antigenic stimulation were investigated. For this purpose germfree BALB/c mice fed an ultrafiltered solution of chemically defined low m.w. nutrients (GF-CD) were used. Previous studies on B cell development and differentiation in GF-CD mice have demonstrated a high reduction in the number of cells secreting Ig of the non-IgM isotypes but an Ig-VH gene usage and a B cell specificity repertoire that is substantially different from that observed in conventional adult mice and more closely resembles that of neonatal conventional mice. In contrast, the present comparison of the various lymphocyte populations in the thymus, lymph nodes, and spleen from GF-CD and conventional mice using flow cytometry analysis revealed no significant differences. Analysis of the TCR-V beta expression on both mature thymocytes and lymph node T cells showed a high degree of similarity between GF-CD and conventional mice. These findings indicate a marked difference in the influence of exogenous antigenic stimulation on the development of B and T cells. Additionally, development in an environment free of exogenous antigenic stimulation allows for full functional maturation of T cells to occur, because MLC showed that GF-CD splenic T cells could mount allogeneic responses in a way similar to T cells generated in a conventional environment. Most importantly, full Th cell function is generated, because activation of GF-CD spleen cells by cross-linking with mAb against CD3 resulted in the induction of cells secreting IFN-gamma and Ig of the non-IgM isotypes, which cannot be detected in GF-CD sera. These findings demonstrate that functional T and B cells develop in mice that have not been exposed to exogenous Ag, and that the TCR repertoire, in contrast to the B cell compartment, is predominantly shaped by endogenously expressed Ag.
Mapping of the rabbit MHC reveals that class I genes are adjacent to the DR subregion and defines an insertion/deletion-related polymorphism in the class II region.
Authors: Chouchane L , Kindt T J 
Published: December 2022

Abstract
Molecular analyses of genes in the rabbit MHC (RLA) by pulsed field gel electrophoresis have shown that the relative order of class II genes (DP, DO, DQ, DR) is identical to that in humans and similar to that in the mouse. However, a major difference from either HLA or H-2 was observed at the DR end of the RLA class II complex: class I genes are located in close proximity to DR with no interposed class III sequences. A MluI fragment of 180 kb and a 210-kb SalI fragment both hybridized with the DR probe as well as with different class I probes including that for pR27, a class I gene with T cell-limited pattern of expression. Comparison of two different RLA haplotypes, A and B, indicated that the distance between the DQ and DR subregions differs by approximately 700 kb in the two haplotypes. Testing other unrelated rabbits suggested that this difference segregates within the rabbit population and presumably derives from an insertion/deletion event in different haplotypes. A further difference between the A and B haplotypes included variable distance between genes encoding DO beta and DP; the DR end of the complex and the class I genes linkage was conserved in the two haplotypes.
Endogenous Mtv-8 or a closely linked sequence stimulates rearrangement of the downstream V kappa 9 gene.
Authors: Yang J N , Dudley J 
Published: December 2022

Abstract
Mtv-8 is an endogenous retrovirus located 4.6 kb upstream of a V kappa region gene (called V kappa 9M) within the kappa-Ig locus. The proximity of these two genes resulted in several effects. Using a newly developed RNase protection assay for measuring transcription from a single endogenous provirus, we found that Mtv-8 transcription could be detected after juxtaposition of the kappa-enhancers to the normally silent provirus. Reciprocally, using the polymerase chain reaction we observed that the frequency of V kappa 9M rearrangement was 5- to 10-fold higher in spleens from Mtv-8-positive mice (BALB/c, C58.C, A/J, and B6) compared to spleens from mice that lacked the Mtv-8 provirus (C58, C.C58, NZB, and PERA/Ei). Molecular cloning and sequencing of the V kappa 9M gene from C.C58 mice (containing the kappa-locus from C58 mice on a BALB/c background) indicated that at least some Mtv-8-negative strains have a functional V kappa 9M gene. Together these data suggest that Mtv-8 or a closely linked gene enhances V kappa 9M rearrangement. Since Mtv-8 also reportedly produces a superantigen, it appears that Mtv-8 may influence both the T cell and B cell repertoires.
IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes.
Authors: Fenton M J , Buras J A , Donnelly R P 
Published: December 2022

Abstract
Activation of human monocytes with LPS induces coordinate expression of a number of cytokine genes, including IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8. The T cell-derived lymphokine, IL-4, inhibits expression of these genes in monocytes, suggesting that it may be an important physiologic regulator of cytokine production. We have previously shown that IL-4 reduces steady state messenger RNA (mRNA) levels for IL-1 beta in human monocytes by decreasing both IL-1 beta transcription and the t1/2 of newly formed IL-1 beta mRNA transcripts. In the present study, we extend these findings to show that IL-4 similarly accelerates the turnover of IL-6 mRNA in LPS-stimulated monocytes. However, this inhibition of cytokine expression and dramatic increase in the decay rate of cytokine mRNA does not extend to all LPS-inducible genes because IL-4 treatment did not inhibit the expression or accelerate the turnover of mRNA for the IL-1 receptor antagonist (IL-1ra) in the same cells. Although IL-1 beta and IL-1Ra are both LPS-inducible genes, they displayed distinct temporal patterns of expression. Peak steady state mRNA levels for IL-1ra lagged significantly behind that of IL-1 beta, suggesting a possible endogenous mechanism for limiting IL-1 biologic activity. Furthermore, although IL-4 suppressed expression of both IL-1 beta and IL-6, it up-regulated synthesis of IL-1ra mRNA and protein. Thus, IL-4 inhibits production of the proinflammatory cytokine, IL-1 beta, while concomitantly enhancing synthesis of the IL-1ra in activated human monocytes.
Recombinant tumor necrosis factor-alpha potentiates neutrophil degranulation in response to host defense cytokines neutrophil-activating peptide 2 and IL-8 by modulating intracellular cyclic AMP levels.
Authors: Brandt E , Petersen F , Flad H D 
Published: December 2022

Abstract
The neutrophil-activating peptide 2 (NAP-2) and IL-8 are closely related in structure and function. In order to further determine their potential biologic roles in inflammation, we studied their interaction with TNF-alpha-primed human polymorphonuclear neutrophil granulocytes at the levels of effector functions and signal transduction. After short term priming (5 min) by TNF-alpha, suspended cytochalasin B-treated PMN responded to NAP-2 or rIL-8 by substantial augmentation of the degranulation response. After priming with 3 ng/ml TNF-alpha marker release from both azurophilic and specific granules was near maximum. NAP-2 and rIL-8 cooperated with TNF-alpha in very similar ways, as indicated by the almost identical increases in release rates that were induced by equipotent doses of either secondary stimulus. At the signal transduction level, pharmacologic elevation of intracellular cAMP led to the inhibition of NAP-2- or rIL-8-induced degranulation in primed and unprimed PMN, indicating a role for this second messenger as a negative feedback signal. Direct measurement of intracellular cAMP revealed that TNF-alpha by itself did not affect its levels. Instead, TNF-alpha reduced both the scale as well as the duration of the cAMP burst generated in response to secondary stimuli NAP-2 or rIL-8. Thus, there is evidence that TNF-alpha priming of neutrophils for enhanced NAP-2- or rIL-8-promoted degranulation involves the antagonistic down-modulation of stimulus-induced rises in cAMP.
Cytokine patterns of immunologically mediated tissue damage.
Authors: Yamamura M , Wang X H , Ohmen J D , Uyemura K , Rea T H , Bloom B R , Modlin R L 
Published: December 2022

Abstract
Reactional states in leprosy are produced by different immunologic mechanisms and are responsible for a major component of tissue damage of the disease. Reversal reactions exhibit increased CD4 T cell infiltration in lesions and augmented cell-mediated immune reactivity to Ag of Mycobacterium leprae that can rapidly produce nerve damage. Erythema nodosum leprosum (ENL) reactions also have CD4 T cell infiltration but appear to be associated with the formation of immune complexes that are responsible for panniculitis, arthritis, vasculitis, and nerve injury. Because these reactional states may serve as paradigms for other types of human immunologically mediated tissue damage, this study sought to characterize the dynamic changes in cytokines associated with these reactions. Expression of cytokine mRNA in lesions of leprosy reactional states were measured by PCR. In reversal reactions, IL-1 beta, TNF-alpha, IL-2, and IFN-gamma mRNA were prominent and found to increase during the reaction, concomitant with decreases in expression of mRNA for IL-4, IL-5, and IL-10. In ENL, selective increases in the expression of IL-6, IL-8, and IL-10 mRNA was observed, with persistent expression of IL-4 and IL-5 mRNA. Reversal reactions represent naturally occurring delayed-type hypersensitivity reactions that favor macrophage activation and protective immunity, but which can engender concomitant cell injury. In contrast, ENL lesions represent immediate-type hypersensitivity reactions reflecting the selective stimulation of cytokines that attract neutrophils, stimulate antibody production, and down-regulate macrophage activation. The analysis of cytokine dynamics within different inflammatory responses can provide insights into immune mechanisms of tissue damage, and provide a useful framework for developing strategies for therapeutic intervention.
Immortalization of murine B cells in vitro with oncogene-containing retroviral vectors.
Authors: Grabstein K H , Hess B , Weisser K E , Clark L , Goodwin R , Overell R W 
Published: December 2022

Abstract
A large panel of oncogene-containing retroviral vectors has been constructed and used to infect activated murine splenic B cells to determine whether particular oncogenes are capable of directly mediating B cell immortalization. Mature B cell lines have been consistently established with some of these retroviral vectors. These B cell lines arose at a low frequency, indicating that more genetic events were required in addition to infection with the retroviral vector for immortalization to occur. All such lines were LPS-dependent and non-tumorigenic. All lines secrete IgG and express surface IgG, but not IgD or IgM. In addition, they are CD11b+ and CD23-. These cells may be derived from the CD5 "lineage" or a related B cell subset and appear to be more susceptible to immortalization than conventional B cells.