bluuebunny/crossref_metadata_2025_split huggingface dataset:
Release of a glycosylphosphatidylinositol-anchored ADP-ribosyltransferase from cytotoxic T cells upon activation.
Authors: Nemoto E , Stohlman S , Dennert G 
Published: December 2022

Abstract
Many cell surface proteins are anchored into the cell membrane by glycosylphosphatidylinositol (GPI), among those a recently discovered arginine-specific mono-ADP-ribosyltransferase on cytotoxic T cells (CTL). This enzyme transfers ADP-ribose to cell surface proteins resulting in inhibition of cytotoxic and proliferative activity. Here we report that ADP-ribosyltransferase is released in active forms by crosslinking CD3, exposure to Il-2 or PMA stimulation. Release of transferase is specific, as another GPI-anchored protein, Thy-1 is not released. Transferase molecules released by cell activation are indistinguishable in size from molecules released by phospholipase C, suggesting that the release mechanism acts close to or within the GPI anchor. Protease inhibitors fail to inhibit transferase release with exception of 1,10-phenanthroline and its 4,7-diphenyl derivative. This suggests that the release mechanism acts on the cell surface but does not discriminate between action of a metalloprotease or phospholipase D. Release of transferase is shown to be rapid, it is not suppressed by monensin or brefeldin A and independent of serum phospholipase D, consistent with a mechanism acting on the cell surface. Transferase expression is shown to be dependent on the cell activation stage. In CTL clones, the transferase is demonstrable as a phospholipase C releasable molecule at early but not later stages of Ag specific activation.
Superantigen-mediated deletion of specific T cell receptor V beta subsets in the SCID-hu Thy/Liv mouse is induced by staphylococcal enterotoxin B, but not HIV-1.
Authors: Komanduri K V , Salha M D , Sékaly R P , McCune J M 
Published: December 2022

Abstract
Infection by HIV-1 has been associated with perturbations in the TCR V beta repertoire, suggesting the involvement of a superantigen. Among the hallmarks of superantigens is the capacity to delete T cells bearing specific TCR V beta families in the developing thymus. To verify the presence of a superantigen in HIV-1, we analyzed the SCID-hu Thy/Liv TCR V beta repertoire within CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocytes subsets by flow cytometry using a panel of Abs recognizing about 60% of the TCR repertoire following injection of SEB or infection by two different HIV-1 isolates. Seven days following SEB injection, thymocyte subsets bearing TCR V beta 3, V beta 12, V beta 17, and V beta 20, but not V beta 5 or V beta 8 , were deleted relative to mock-injected mice. In contrast, no changes were observed in the TCR V beta repertoire in CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocyte subsets after infection with HIV-1. The T cell depletion caused by HIV-1 infection is most likely not mediated by an HIV-encoded superantigen.
Recognition of a B cell leukemia-associated minor histocompatibility antigen by CTL.
Authors: Dolstra H , Fredrix H , Preijers F , Goulmy E , Figdor C G , de Witte T M , van de Wiel-van Kemenade E 
Published: December 2022

Abstract
CTL directed against minor histocompatibility Ags (mHag) play a major role in antileukemia reactivity after HLA-identical bone marrow transplantation. Some of these mHag are restricted to hemopoietic cells, others show a broad tissue expression. Therefore, antileukemia reactivity is often associated with graft-vs-host disease. Here, we report the identification of a B cell leukemia-associated mHag, HB-1, recognized by a CD8+ CTL clone derived from peripheral blood of an acute lymphoblastic B cell leukemia patient who has been treated by HLA-matched bone marrow transplantation. Interestingly, the CTL clone that recognizes HB-1 exhibits specific cytotoxicity toward leukemic as well as EBV-transformed B cells, but not against untransformed B cells. Moreover, the CTL clone does not lyse PHA-stimulated T cell blasts, monocytes, and fibroblasts, indicating that HB-1 is mainly expressed by transformed B cells. Further analysis reveals that HB-1 is restricted by HLA-B44 (both B*4402 and B*4403) and that 28% of HLA-B44-positive individuals express HB-1. These findings demonstrate that leukemia-associated mHag with a restricted tissue distribution, such as HB-1, elicit CTL reactivity in vivo. These Ags are of potential use in immunotherapy against leukemia because they generate antileukemia reactivity that is not associated with graft-vs-host disease.
IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells.
Authors: Nikcevich K M , Gordon K B , Tan L , Hurst S D , Kroepfl J F , Gardinier M , Barrett T A , Miller S D 
Published: December 2022

Abstract
Astrocytes may serve as effectual APCs for T cell-mediated immune responses to myelin components during multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Although astrocytes have been reported not to constitutively express MHC class II molecules, expression is up-regulated during active EAE and by in vitro incubation with IFN-gamma. Previous studies have reported that cytokine-activated astrocytes are able to activate Ag-specific previously activated T cells, but not naive alloreactive T cells. In the current study, we show that a subset of primary murine astrocytes constitutively expresses B7-2 molecules, as determined by FACS and PCR analyses, and up-regulates surface expression and mRNA levels of both B7-2 and B7-1 upon IFN-gamma stimulation. In contrast to earlier reports, we found that both untreated and IFN-gamma-treated astrocytes were able to stimulate proliferation of previously activated OVA-specific Th1 cells. In contrast, only IFN-gamma-treated astrocytes activated naive, transgenic OVA-specific T cells. Astrocyte-induced activation of both OVA-specific naive T cells and activated Th1 cells was dependent primarily on B7-2-mediated costimulation, as proliferation was inhibited by CTLA4-Ig and by anti-B7-2 mAbs. These results suggest that astrocytes in an inflammatory environment have the capacity to express the required MHC class II and B7 costimulatory molecules necessary for efficient activation of naive T cells. Since we have shown that T cells specific for endogenous myelin epitopes released during acute EAE play the major pathologic effector role in subsequent disease relapses (epitope spreading), astrocytes could play a role in the local activation and expansion of these responses.
Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-gamma-producing cells.
Authors: Piccotti J R , Chan S Y , Li K , Eichwald E J , Bishop D K 
Published: December 2022

Abstract
The role of IL-12 role in regulating Th1/Th2 balance is attributed in part to the ability of this cytokine to induce IFNgamma production by NK and Th1 cells, which in turn promotes Th1 and inhibits Th2 development. In the present study, the requirement for IL-12 in the development of alloantigen-reactive Th1 was assessed by adding neutralizing anti-IL-12 Abs or the IL-12 receptor antagonist p40 homodimer to primary MLC. The resulting cell populations were assessed for Th1 development by measuring IFN-gamma production upon restimulation with alloantigens. While the addition of anti-IL-12 Abs to primary MLC did not influence subsequent cytokine production, addition of p40 homodimer markedly enhanced, rather than decreased, Th1 development. To determine which T cell population produced enhanced levels of IFN-gamma in response to p40 homodimer, CD4+ or CD8+ T cells were depleted from the MLC. While p40 homodimer was inhibitory to selected CD4+ Th1 development, it enhanced IFN-gamma production by CD8+ T cells. To test the in vivo relevance of these findings, mouse heterotopic cardiac allograft recipients were treated with either p40 homodimer, anti-CD8 mAb, or with both p40 homodimer and anti-CD8 mAb. Treatment of allograft recipients with p40 homodimer had no effect on the in vivo sensitization of IFN-gamma-producing cells and resulted in accelerated allograft rejection relative to unmodified recipients. However, p40 homodimer markedly prolonged allograft survival in mice depleted of CD8+ T cells. Hence, p40 homodimer stimulates CD8+ Th1 development in vitro but inhibits CD4+ T cell function both in vitro and in vivo.
Presentation of an influenza nucleoprotein epitope incorporated into the H-2Db signal sequence requires the transporter-associated with antigen presentation.
Authors: Uger R A , Barber B H 
Published: December 2022

Abstract
In an effort to optimize the formation of peptide-specific CTL target structures in the context of plasmid DNA immunization, a strategy was developed to couple the biosynthesis of a class I heavy chain with its optimal binding epitope. Specifically, a cDNA expression vector was constructed with the influenza nucleoprotein epitope NP366-74 incorporated into the signal sequence of its restriction element H-2Db. Transporter associated with Ag presentation-expressing murine cell lines P815 (H-2d) and BW5147 (H-2k) transfected with this modified heavy chain expressed normal levels of plasmid-encoded Db at the cell surface, and were lysed by NP366-74-specific CTL. These results indicate that the modified signal sequence was successfully delivered to the endoplasmic reticulum, and the epitope within it processed for T cell recognition. In contrast, T2 cells, which lack the TAP transporter, when transfected with the same vector were not lysed by NP366-74 CTL, and exhibited an Ag-processing-defective phenotype. Thus, these data, which indicate TAP-dependent presentation of an optimal CTL epitope located in a signal sequence, challenge the effectiveness of Ag processing in the endoplasmic reticulum.
Effect of serum IgG1 to Cryptococcus neoformans glucuronoxylomannan on murine pulmonary infection.
Authors: Feldmesser M , Casadevall A 
Published: December 2022

Abstract
Little is known about the role of Ab in protection against pulmonary fungal pathogens. The ability of murine IgG1 mAb 2H1 to modify pulmonary Cryptococcus neoformans infection was investigated in intratracheal infection. mAb 2H1 binds C. neoformans glucuronoxylomannan. mAb 2H1 was given to A/JCr mice 24 h before infection. Two C. neoformans strains were studied: ATCC 24067 (serotype D) and 62070 (serotype A). Fungal burden was determined by CFU 14 days after infection for both strains, and at 2 h, 24 h, 48 h, 7 days, and 28 days after infection for strain 24067. On day 14, mAb 2H1 treatment reduced CFU in the lung, brain, and liver for strain 62070 infection. Minor reductions in lung CFU followed infection with strain 24067 in mAb 2H1-treated mice, despite prolonged survival. The limited ability of mAb 2H1 to reduce lung CFU may reflect rapid phagocytosis of yeast by alveolar macrophages, seen by electron microscopy 2 h after infection, regardless of whether mice had received mAb. Alveolar macrophages phagocytosed and reduced C. neoformans CFU in vitro only in the presence of mAb 2H1. Differences were apparent in phagocytosis and in vitro killing between strains 24067 and 62070. Serum IgG1 modified the course of pulmonary infection in mice by prolonging survival, reducing CFU, and reducing tissue glucuronoxylomannan Ag. mAb administration was associated with enhanced granulomatous inflammation, but did not prevent infection or dissemination. Despite incomplete protection by serum Ab against pulmonary infection, our results provide encouragement for continued vaccine development.
IL-15, an immunomodulator of T cell responses in intracellular infection.
Authors: Jullien D , Sieling P A , Uyemura K , Mar N D , Rea T H , Modlin R L 
Published: December 2022

Abstract
IL-15 is a novel cytokine with potent T cell growth factor activity. Here, we investigated the role of IL-15 in the human immune response to intracellular infection by studying patients leprosy. We found that IL-15 mRNA and protein were more strongly expressed in immunologically resistant tuberculoid patients than in with unresponsive and susceptible lepromatous patients. In vitro, Mycobacterium leprae induced IL-15 secretion from peripheral blood monocytes. Furthermore, rIL-15 by itself and in combination with rIL-2 or rIL-7 augmented PBMC proliferative responses to the pathogen. Although rIL-15 expanded the CD3-CD56+ (NK) subset, rIL-15 combined with M. leprae induced the expansion of CD3+CD56+ T cells. Immunohistologic analysis of leprosy skin lesions indicated that the frequency of CD56+ cells was greatest in the group of patients with high IL-15 expression, and that &gt;90% of the CD56+ cells in lesions were CD3+ T cells. Therefore, IL-15 augments the local T cell response to human intracellular pathogen.
B7-negative versus B7-positive P815 tumor: differential requirements for priming of an antitumor immune response in lymph nodes.
Authors: Yang G , Mizuno M T , Hellström K E , Chen L 
Published: December 2022

Abstract
Efficient T cell activation requires two synergistic but distinct signals derived from antigenic peptides presented by the MHC and from costimulatory molecules, particularly those belonging to the B7 family. Lack of B7-CD28 interaction may cause unresponsiveness of T cells to subsequent exposure to Ag. Nevertheless, immunization by some B7- tumors induces an antitumor immune response. We found that the immune response against two B7- tumors, the mouse P815 mastocytoma and the E7C3 melanoma, requires host-derived B7, since blockage of the B7-CD28 interaction facilitates tumor growth and eliminates an antitumor response. B7 costimulation is provided in the regional, tumor-draining lymph nodes for the induction of a primary CTL response against both B7+ tumor and B7- tumor. However, the induction of a CTL response to B7+ tumors and its clonal expansion may occur at tumor sites in addition to secondary lymphoid organs so as to generate more effective tumor immunity.
Eosinophils transcribe and translate messenger RNA for inducible nitric oxide synthase.
Authors: del Pozo V , de Arruda-Chaves E , de Andrés B , Cárdaba B , López-Farré A , Gallardo S , Cortegano I , Vidarte L , Jurado A , Sastre J , Palomino P , Lahoz C 
Published: December 2022

Abstract
Because of the involvement of nitric oxide (NO) in inflammatory states such as parasitic and hypersensitivity disorders and the fact that eosinophils are one of the cell types implicated, we asked whether eosinophils were able to express mRNA specific to inducible NO synthase (iNOS) and iNOS protein and to secrete nitric oxide. iNOS protein was detected on eosinophil preparations by immunocytochemistry using iNOS mAb. Expression of iNOS protein was also detected by immunoblotting in human purified eosinophils and an eosinophilic leukemia cell line, Eol-3. Nitrite production was detected in the supernatant of human eosinophils and Eol-3 cells cultured for 24 h, and was completely inhibited in the presence of the NOS inhibitor N-methylester-L-arginine. iNOS cDNA was obtained by reverse transcription-PCR. After subcloning, sequencing of the 259-bp fragment from three different human eosinophils cDNAs revealed 97% identity with macrophage/monocyte iNOS. Our studies describe for the first time the presence of iNOS on eosinophil and a putative new role for this cell in inflammatory states such as asthma and parasitic disease.
Association of non-receptor protein tyrosine kinases with the Fc gamma RI/gamma-chain complex in monocytic cells.
Authors: Duchemin A M , Anderson C L 
Published: December 2022

Abstract
To characterize the functional macromolecular complex of the high affinity receptor for IgG (Fc gamma RI), we have undertaken the identification of the molecules associated with the ligand binding unit and its associated subunit, gamma-chain, in a monocyte cell line, U937. Comparison of the pattern of tyrosine-phosphorylated proteins that coprecipitate with anti-Fc gamma RI or anti-gamma-chain Abs after Fc gamma RI clustering suggests that, like other receptor systems, the different units of the receptor associate or recruit different elements of the signaling pathway. Syk associates preferentially with the gamma-chain subunit and not with Fc gamma RI itself. This association is dependent on receptor clustering and correlates with gamma-chain phosphorylation. The Src kinase Lyn is also part of the receptor complex. Lyn associates with both units of the receptor, and this association is independent of receptor engagement; however, the level of tyrosine phosphorylation of the kinase increases after Fc gamma RI clustering. Association of a 35-kDa phosphoprotein with the binding unit was also observed after receptor clustering. We further found that after Fc gamma RI clustering, tyrosine-phosphorylated Syk associates with Lyn. These data suggest that several levels of interaction occur between these molecules or that different pools of tyrosine kinases become activated after Fc gamma RI clustering.
An increase in intracellular cyclic AMP modulates nitric oxide production in IFN-gamma-treated macrophages.
Authors: Mullet D , Fertel R H , Kniss D , Cox G W 
Published: December 2022

Abstract
Macrophages treated with IFN-gamma alone are stimulated to produce nitric oxide. The level of nitric oxide production can be enhanced significantly when IFN-gamma treatment is combined with other agents (e.g., LPS, TNF-alpha, IL-2, etc.). We tested the hypothesis that cAMP plays a role in the IFN-gamma-induced activation of macrophages. Our experiments indicate that factors that increase the concentration of cAMP in the murine macrophage cell line ANA-1 can also enhance IFN-gamma-induced production of nitric oxide. PGE2 and cholera toxin increased the production of nitrite (an indicator of nitric oxide production) in IFN-gamma-treated ANA-1 macrophages by at least twofold. These factors produced no increase in nitric oxide production in the absence of IFN-gamma treatment. The increase in nitric oxide production corresponded to an increase in the accumulation of nitric oxide synthase mRNA without a change in stability of mRNA. Dibutyryl cAMP and Sp-cAMPs (a selective activator of cAMP-dependent protein kinase I and II) also increased nitric oxide production in IFN-gamma-treated macrophages. However, at very high concentrations (i.e., &gt;100 microM), the stimulatory effect was decreased. These studies indicate that elevation of intracellular cAMP causes a dose-dependent, biphasic alteration of IFN-gamma-induced nitric oxide production in murine macrophages. Moreover, they suggest that agents that affect nitric oxide synthesis may do so via modulation of the cAMP second messenger system.
Neutrophil apoptosis is modulated by endothelial transmigration and adhesion molecule engagement.
Authors: Watson R W , Rotstein O D , Nathens A B , Parodo J , Marshall J C 
Published: December 2022

Abstract
Termination of a neutrophil-mediated inflammatory response occurs through the activation of the endogenous cell death program, apoptosis. Neutrophil apoptosis is a constitutive process that can be accelerated or delayed by signals from the microenvironment. Since cellular localization at the site of an inflammatory challenge is the critical first step in a neutrophil response, we investigated the effects of neutrophil transendothelial transmigration on the kinetic expression of apoptosis. Neutrophils isolated from rat lung following challenge with LPS demonstrated a significant delay in spontaneous apoptosis. This delay was a consequence of transmigration, since a comparable delay was seen when TNF-alpha, a potent inducer of apoptosis in vitro, was used as the inflammatory stimulus. Human neutrophils demonstrated comparable delays in apoptosis in vitro following migration across an endothelial monolayer in response to FMLP. Delayed apoptosis only occurred in cells that had first been primed by LPS, a stimulus shown to up-regulate beta2 integrins and down-regulate L-selectin. Finally, crosslinking of CD11a or CD11b, but not of CD18, with mAbs and F(ab')2 fragments produced a delay in spontaneous apoptosis, whereas crosslinking of L-selectin with mAb or its natural ligand, sulfatides, accelerated the apoptotic process. Cells in which apoptosis was inhibited demonstrated persistent functional respiratory burst activity. These observations establish a role for endothelial transmigration in the regulation of neutrophil apoptosis, and suggest that adhesion molecules serve a modulatory role in the expression of neutrophil programmed cell death.
Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.
Authors: Hayward A R , Levy J , Facchetti F , Notarangelo L , Ochs H D , Etzioni A , Bonnefoy J Y , Cosyns M , Weinberg A 
Published: December 2022

Abstract
We report an association between X-linked immunodeficiency with hyper-IgM (XHIM) and carcinomas affecting the liver, pancreas, biliary tree, and associated neuroectodermal endocrine cells. The tumors were fatal in eight of nine cases and in most instances were preceded by chronic cholangiopathy and/or cirrhosis. An additional group of subjects with XHIM had chronic inflammation of the liver or bile ducts but no malignancy. Many patients with XHIM were infected with cryptosporidia. CD40 is normally expressed on regenerating or inflammed bile duct epithelium. A CD40+ hepatocellular carcinoma cell line, HepG2, susceptible to cryptosporidia and CMV infection became resistant when cell surface CD40 was cross-linked by a CD40 ligand fusion protein. Apoptosis was triggered in HepG2 cells if protein synthesis was blocked by cycloheximide or if the cells were infected by cryptosporidia. Ligation of CD40 on biliary epithelium may contribute to defense against infection by intracellular pathogens. We propose that the CD40 ligand mutations that cause XHIM deprive the biliary epithelium of one line of defense against intracellular pathogens and that malignant transformation in the biliary tree follows chronic infection or inflammation. The resulting tumors may then progress without check by an effective immune response. Patients with XHIM who have abnormal liver function tests should be considered at increased risk for cholangiopathy or malignancy.
Therapeutic effect of DNA immunization of genetically susceptible mice infected with virulent Mycoplasma pulmonis.
Authors: Lai W C , Pakes S P , Ren K , Lu Y S , Bennett M 
Published: December 2022

Abstract
Genetically susceptible BALB/c mice were immunized i.m. with DNA for one or two Mycoplasma pulmonis Ags (A7-1, A8-1) beginning either 1 wk before (vaccination) or 1 wk after (treatment) intranasal infection with 5 x 10(4) CFU virulent M. pulmonis organisms. Immunization of mice by this method induced both humoral and cellular immunity to M. pulmonis, largely prevented infection (vaccination), and cleared an ongoing pneumonia over time (treatment). Only one Ag gene was required. Thus, DNA immunization is a potential treatment for infections and may be useful in instances when drug therapy may not be available or effective.