bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of the T Cell Response to Immunodominant Determinants Within Hen Eggwhite Lysozyme of Individual Syngeneic Hybrid F1 Mice: Implications for Autoimmunity and Infection
Authors: Moudgil Kamal D. , Wang Jay , Yeung Valentine P. , Sercarz Eli E. 
Published: January 2023

AbstractHybrid F1 mice derived from inbred parental mouse strains are extensively used as animal models of human autoimmune diseases and transplantation. It is generally believed that with regard to immunologic studies, hybrid F1 mice behave in a consistent manner, equivalent to any other inbred mouse strain. In this study, we report that in comparison to inbred parental strains, individual hybrid F1 mice revealed a broad heterogeneity of proliferative response to the immunodominant determinants within hen eggwhite lysozyme (HEL). Of five parental strains tested, individual mice of three strains responding to only a few dominant HEL determinants (B6, BALB/c, and B10.PL) showed quite homogeneous patterns of response, whereas two mouse strains responsive to several determinants of HEL revealed either relative homogeneity (CBA/J mice) or heterogeneity (SJL mice) of response. However, in SJL mice, responses to major, dominant determinants of HEL were quite consistent. On the contrary, regardless of the consistency of response of parental strains, all three of F1 mice {[B6 × BALB/c]F1, [B6 × CBA/J]F1, and [SJL × B10.PL]F1} revealed significantly greater heterogeneity of response, which even involved the major, dominant determinants of HEL. We attribute the above heterogeneity of response to the competitive as well as aleatory nature of the interaction between various factors, including the coexistence of different MHC (parental as well as hybrid MHC) molecules, determinant capture, and the T cell repertoire. These results have important implications for studies on autoimmunity, infection, and vaccine design in human populations, where heterozygosity is the norm rather than the exception.
Cooperative Activation of TCRs by Enterotoxin Superantigens
Authors: Niedergang Florence , Dautry-Varsat Alice , Alcover Andrés 
Published: January 2023

Abstract
Staphylococcus enterotoxin superantigens are potent T cell activators. To gain new insights into the mechanism of T cell activation induced by these superantigens, we investigated the recruitment of signaling molecules in this process. Here, we show that enterotoxin superantigen activation can be transmitted to TCR-CD3 complexes that did not interact with their ligand. Indeed, by studying cells expressing two distinct TCRs, we found that enterotoxin superantigens induced tyrosine phosphorylation of TCRζ subunits, the recruitment and tyrosine phosphorylation of the protein tyrosine kinase ZAP-70, and an increase in protein tyrosine kinase activity of both directly stimulated and unstimulated TCR-CD3 complexes. As the involvement of unstimulated TCR-CD3 complexes in signal transduction would increase the number of signaling molecules and, therefore, the efficiency of T cell activation, these data provide a novel explanation for the ability of enterotoxin superantigens to potently activate T lymphocytes.
Decreased Frequency of Rearrangement due to the Synergistic Effect of Nucleotide Changes in the Heptamer and Nonamer of the Recombination Signal Sequence of the Vκ Gene A2b, Which Is Associated with Increased Susceptibility of Navajos to Haemophilus influenzae Type b Disease
Authors: Nadel Bertrand , Tang Alan , Lugo Geanncarlo , Love Victoria , Escuro Guia , Feeney Ann J. 
Published: January 2023

Abstract
Navajos and genetically related populations have a 10-fold increased incidence of Haemophilus influenzae type b (Hib) disease compared with control populations. The Vκ gene A2 is used to encode the majority of anti-Hib Abs, and these are the highest affinity anti-Hib Abs. Navajos carry a different allele of the A2 gene segment (A2b) that is defective in its ability to undergo V-J recombination. The A2b allele has only three nucleotide changes from the commonly occurring A2a allele, two of which could potentially affect its ability to recombine. In this study we used two independent in vitro assays to test whether the nucleotide change found in the A2b promoter and/or in the A2b recombination signal sequence (RSS) might be responsible for the decrease in recombination frequency observed in vivo. Using a luciferase reporter gene assay, we found no significant difference between A2a and A2b promoter activities. However, the competition recombination substrate assay showed a 4.5-fold reduction in the relative frequency of recombination of the A2b RSS compared with A2a. We show that this decreased frequency is due to a synergistic effect of the unique nucleotide change present in the heptamer of the A2b RSS and the shared nucleotide change present in the nonamer of both A2b and A2a. This in vitro relative frequency of rearrangement is not significantly different from that observed in vivo; therefore, the A2b RSS is probably the factor associated with the increased susceptibility to Hib disease among individuals carrying the A2b allele.
Cloning and Characterization of the Guinea Pig Eosinophil Eotaxin Receptor, C-C Chemokine Receptor-3: Blockade Using a Monoclonal Antibody In Vivo
Authors: Sabroe Ian , Conroy Dolores M. , Gerard Norma P. , Li You , Collins Paul D. , Post Theodore W. , Jose Peter J. , Williams Timothy J. , Gerard Craig J. , Ponath Paul D. 
Published: January 2023

AbstractCertain C-C chemokines, signaling via the eotaxin receptor C-C chemokine receptor-3 (CCR3), are thought to be central mediators of eosinophil accumulation in allergic inflammation. To investigate the role of CCR3 in vivo, we cloned the guinea pig eotaxin receptor (guinea pig CCR3) from a genomic DNA library. We isolated a single-exon open reading frame coding for a 358-amino acid chemokine receptor protein with 67 and 69% homology to human and murine CCR3, respectively. When expressed in stable transfectants, this receptor bound 125I-labeled guinea pig eotaxin, 125I-labeled human monocyte chemotactic protein-3, and 125I-labeled human RANTES. In chemotaxis assays, guinea pig CCR3 transfectants responded only to guinea pig eotaxin, with a maximal effect at 100 nM. mAbs were raised that bound selectively to both guinea pig CCR3 transfectants and guinea pig eosinophils. One of these mAbs, 2A8, blocked both ligand binding to transfectants and their chemotaxis in response to eotaxin. The Ab also inhibited chemotaxis and the elevation of cytosolic calcium in guinea pig eosinophils in response to eotaxin. F(ab′)2 fragments of 2A8 were prepared that retained the ability to inhibit eosinophil calcium responses to eotaxin. Pretreatment of 111In-labeled eosinophils in vitro with F(ab′)2 2A8 selectively inhibited their accumulation in response to eotaxin in vivo. These data demonstrate that functional blockade of eosinophil chemokine receptors can be achieved in vivo and provide further support for the development of novel anti-inflammatory drugs targeting eosinophil recruitment through chemokine receptor antagonism.
IL-10 Is Required for Development of Protective Th1 Responses in IL-12-Deficient Mice uponCandida albicansInfection
Authors: Mencacci Antonella , Cenci Elio , Sero Giuseppe Del , Fé d’Ostiani Cristiana , Mosci Paolo , Trinchieri Giorgio , Adorini Luciano , Romani Luigina 
Published: January 2023

AbstractIL-12 is both required and prognostic for Th1 development in mice with Candida albicans infection. To delineate further the physiologic role of IL-12 in antifungal immunity, mice deficient for this cytokine were assessed for susceptibility to C. albicans infections, and for parameters of innate and adaptive immunity. IL-12-deficient mice were highly susceptible to gastrointestinal infection or to reinfection and showed elevated production of Candida-specific IgE and IL-4 and defective production of IFN-γ. The failure to mount protective Th1 responses occurred despite the presence of an unimpaired innate antifungal immune response, which correlated with unaltered IFN-γ production, but defective production of, and responsiveness to, inhibitory IL-10. IL-10 or IL-12 neutralization increased the innate antifungal resistance in wild-type mice. However, in IL-12-deficient mice, treatment with exogenous IL-12 or IL-10 impaired IL-4 production and increased resistance to infection, through a negative effect on the CTLA-4/B7-2 costimulatory pathway. These results confirm the obligatory role of IL-12 in the induction of anticandidal Th1 responses, and indicate the existence of a positive regulatory loop between IL-12 and IL-10 that may adversely affect the innate antifungal response, but is required for optimal costimulation of IL-12-dependent CD4+Th1 cells.
Mast Cells Express Novel CD8 Molecules That Selectively Modulate Mediator Secretion
Authors: Lin Tong-Jun , Hirji Nadir , Nohara Osamu , Stenton Grant R. , Gilchrist Mark , Befus A. Dean 
Published: January 2023

Abstract
CD8, a marker largely restricted to subsets of T lymphocytes and NK cells, was detected on freshly isolated rat peritoneal mast cells (PMC). Using flow cytometry, Percoll-enriched rat PMC (≥98% purity) were positive for the hinge region of CD8α (67.5 ± 9.5%; Ab OX8) and CD8β (27.8 ± 2.3%; Ab 341). CD8+ PMC consisted of two populations, CD8α+ (22.5%) and CD8α+β+ (15.9%). Interestingly, G28, an Ab that identifies the IgV-like region of CD8α on T lymphocytes, did not bind PMC, suggesting that PMC CD8α is distinct from that on T lymphocytes. Moreover, a similar pattern of Ab positivity for CD8 was observed on a rat mast cell line, RBL 2H3. The presence of CD8α immunoreactivity on rat PMC was further confirmed by confocal microscopy. In situ reverse-transcription PCR and reverse-transcription PCR analysis demonstrated that PMC contained mRNA transcripts encoding CD8α. In functional studies of CD8 on PMC, both TNF-α and nitric oxide production were induced by OX8 (CD8α) and 341 Ab (CD8β) in a dose-dependent manner. However, neither OX8 nor 341 induced histamine secretion from PMC. Ag-induced secretion of TNF-α, nitric oxide, and histamine was not affected by OX8 or 341 Abs, suggesting that there are distinct signaling mechanisms mediated by CD8 and FcεRI. These results indicate that rat PMC express functional CD8 molecules that may be distinct from those of T lymphocytes. The difference suggests there is a ligand other than MHC class I for mast cell CD8.
Immunomodulatory Effects of Hypertonic Resuscitation on the Development of Lung Inflammation Following Hemorrhagic Shock
Authors: Rizoli Sandro B. , Kapus Andras , Fan Jie , Li Yue H. , Marshall John C. , Rotstein Ori D. 
Published: January 2023

Abstract
Hypertonic resuscitation fluids are known to be effective in restoring circulating volume in the hypovolemic trauma patient. Previous studies have suggested that hypertonicity might exert effects on immune cells leading to an altered host response. The present studies evaluated the effect of hypertonic resuscitation on the development of lung injury in a hemorrhagic shock model in which antecedent shock primes for increased lung neutrophil sequestration in response to intratracheal LPS. Resuscitation with hypertonic saline significantly reduced albumin leak, bronchoalveolar lavage fluid neutrophil counts, and the degree of histopathologic injury compared with resuscitation with Ringer’s lactate. Both in vivo and in vitro data suggest that this beneficial effect may be related to altered adhesion molecule expression by the neutrophil. Specifically, hypertonicity induced shedding of L-selectin and prevented LPS-stimulated expression and activation of CD11b, both of which might contribute to reduced sequestration in the lung. Impaired up-regulation of lung ICAM-1 may have also participated, although ex vivo studies suggest that alterations in neutrophils were sufficient to account for the effect. Lung cytokine-induced neutrophil chemoattractant did not differ between animals resuscitated with hypertonic saline vs Ringer’s lactate. Considered together, these studies demonstrate a possible novel approach to inhibiting organ injury in disease processes characterized by neutrophil-mediated damage.
Costimulation Through CD86 Is Involved in Airway Antigen-Presenting Cell and T Cell Responses to Allergen in Atopic Asthmatics
Authors: Larché Mark , Till Stephen J. , Haselden Brigitte M. , North Janet , Barkans Julia , Corrigan Christopher J. , Kay A. Barry , Robinson Douglas S. 
Published: January 2023

AbstractAtopic allergic asthma is characterized by activation of Th2-type T cells in the bronchial mucosa. Previous reports have suggested an important role for costimulation through the CD28/CTLA4-CD80/CD86 pathway in allergen activation of T cells in animal models of inhaled allergen challenge. However, human allergen-specific lines and clones were reported to be costimulation independent. We therefore examined CD80 and CD86 dependence of allergen-induced T cell proliferation and cytokine production in peripheral blood and bronchoalveolar lavage from atopic asthmatic subjects and controls. Both allergen-induced proliferation and IL-5 production from PBMC were inhibited by CTLA4-Ig fusion protein and anti-CD86, but not anti-CD80 mAbs. When allergen-specific CD4+ T cell lines from peripheral blood were examined, proliferation and cytokine production were found to be independent of CD80 or CD86 costimulation. However, when cells obtained directly from the airways were examined, allergen-induced proliferation of bronchoalveolar lavage T cells from atopic asthmatic subjects was inhibited by anti-CD86 but not anti-CD80. In addition, bronchoalveolar lavage-adherent cells from asthmatic, but not control subjects showed APC activity to autologous T cells. This was also inhibited by anti-CD86 but not anti-CD80. Thus allergen-induced T cell activation and IL-5 production in the airway in asthmatic subjects is susceptible to blockade by agents interfering with costimulation via CD86, and this may hold therapeutic potential in asthma.
A Novel Factor Produced by Placental Cells with Activity Against HIV-1
Authors: Sharma Usha K. , Trujillo Jorge , Song Hai-Feng , Saitta Francis P. , Laeyendecker Oliver B. , Castillo Renan , Arango-Jaramillo Silvio , Sridharan Gopalan , Dettenhofer Markus , Blakemore Karen , Yu Xiao-Fang , Schwartz David H. 
Published: January 2023

Abstract
The factors controlling the dynamics of HIV-1 transmission from mother to infant are not clearly known. Previous studies have suggested the existence of maternal and placental protective mechanisms that inhibit viral replication in utero. Preliminary studies from our laboratory revealed that supernatant from placental stromal cells protected HIV-1-infected PBMC from virus-induced apoptosis and suppressed virus production. We have attempted to characterize the antiviral activity of this placental factor (PF) and delineate the stages of HIV-1 replication affected. This activity was not due to the presence of any known cytokine reported to have anti-HIV effect. Direct exposure to PF had no suppressive effect on the infectivity of cell-free HIV-1, and envelope-mediated membrane fusion appeared to be unaffected. Western blot analysis of HIV-1 from infected PBMC treated with PF revealed that expression of all viral proteins was reduced proportionately, both intracellularly and in released virions. However, exposure of HIV-1-infected cells to PF resulted in production of virions with 10–100-fold-reduced infectivity. PF-treated virions contained two- to threefold reduced ratios of cyclophilin A:Gag protein as compared with untreated virus. Reduced cyclophilin A content resulting in decreased binding of cyclophilin A to Gag could account, in part, for the observed reduction in infectivity. Our results suggest that placental cells produce an antiviral factor that protects the fetus during gestation and may have therapeutic potential.
Exceptional Stability of the HLA-DQA1*0102/DQB1*0602 αβ Protein Dimer, the Class II MHC Molecule Associated with Protection from Insulin-Dependent Diabetes Mellitus
Authors: Ettinger Ruth A. , Liu Andrew W. , Nepom Gerald T. , Kwok William W. 
Published: January 2023

AbstractHLA-DQ alleles are closely associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) but the immunologic mechanisms involved are not understood. Structural studies of the IDDM-susceptible allele, HLA-DQA1*0301/DQB1*0302, have classified it as a relatively unstable dimer, particularly at neutral pH. This is reminiscent of studies in the nonobese diabetic mouse, in which I-Ag7 is relatively unstable, in contrast to other murine I-A alleles, suggesting a correlation between unstable MHC class II molecules and IDDM susceptibility. We have addressed this question by analysis of dimer stability patterns among various HLA-DQ molecules. In EBV-transformed B-lymphoblastoid cell lines and PBL, the protein encoded by the IDDM-protective allele HLA-DQA1*0102/DQB1*0602 was the most SDS stable when compared with other HLA-DQ molecules, including HLA-DQA1*0102/DQB1*0604, a closely related allele that is not associated with protection from IDDM. Expression of six different HLA-DQ allelic proteins and three different HLA-DR allelic proteins in the bare lymphocyte syndrome cell line, BLS-1, revealed that HLA-DQA1*0102/DQB1*0602 is SDS stable even in the absence of HLA-DM, while other HLA class II molecules are not. These results suggest that the molecular property of HLA-DQ measured by resistance to denaturation of the αβ dimer in SDS may play a role in IDDM protection.
Cutting Edge: Requirement of Class I Signal Sequence-Derived Peptides for HLA-E Recognition by a Mouse Cytotoxic T Cell Clone
Authors: Martinozzi Silvia , Pacasova Rita , Boulouis Henri-Jean , Ulbrecht Matthias , Weiss Elisabeth H. , Sigaux François , Pla Marika 
Published: January 2023

AbstractThe human nonclassical MHC class I molecule HLA-E has recently been shown to act as a major ligand for NK cell inhibitory receptors. Using HLA-E-expressing transgenic mice, we produced a cytotoxic T cell clone that specifically recognizes the HLA-E molecule. We report here that this T cell clone lyses HLA-E-transfected RMA-S target cells sensitized with synthetic class I signal sequence nonamers. Moreover, this T cell clone lyses human EBV-infected B lymphocytes, PHA blasts, and PBL, formally demonstrating the surface expression of HLA-E/class I signal-derived peptide complex on human cells. Furthermore, these data show that HLA-E complexed with class I signal sequence-derived peptides is not only a ligand for NK cell inhibitory receptors, but can also trigger cytotoxic T cells (CTL).
ChT1, an Ig Superfamily Molecule Required for T Cell Differentiation
Authors: Katevuo Kaisa , Imhof Beat A. , Boyd Richard , Chidgey Ann , Bean Andrew , Dunon Dominique , Göbel Thomas W. F. , Vainio Olli 
Published: January 2023

Abstract
The thymus is colonized by circulating progenitor cells that differentiate into mature T cells under the influence of the thymic microenvironment. We report here the cloning and function of the avian thymocyte Ag ChT1, a member of the Ig superfamily with one V-like and one C2-like domain. ChT1-positive embryonic bone marrow cells coexpressing c-kit give rise to mature T cells upon intrathymic cell transfer. ChT1-specific Ab inhibits T cell differentiation in embryonic thymic organ cultures and in thymocyte precursor cocultures on stromal cells. Thus, we provide clear evidence that ChT1 is a novel Ag on early T cell progenitors that plays an important role in the early stages of T cell development.
Relationship Between Chimerism and Tolerance in a Kidney Transplantation Model
Authors: Fuchimoto Yasushi , Yamada Kazuhiko , Shimizu Akira , Yasumoto Akihiko , Sawada Tokihiko , Huang Christene H. , Sachs David H. 
Published: January 2023

Abstract
The persistence of donor leukocytes in recipients of organ allografts has been associated with long-term graft acceptance. However, it remains unclear whether this peripheral donor cell microchimerism plays an active role in graft acceptance or is simply a consequence of the maintenance of sufficient immunosuppression to avoid rejection. A model of kidney transplantation between swine leukocyte Ag (SLA)-matched miniature swine, in which tolerance can be established with or without immunosuppressive treatment, has been used to study the correlation between donor leukocyte chimerism and kidney graft acceptance. SLA-identical kidney transplants were performed from animals positive for an allelic pig leukocyte Ag to animals negative for this marker. SLA-identical kidney transplant recipients given a 12-day course of cyclosporine (CyA) (n = 3) became tolerant, showing stable serum creatinine levels (1–2 mg/dl) after cessation of CyA treatment. Donor cell chimerism (0.2–0.7%) was present by FACS in all three animals with peak levels detected at 3 wk. Two control animals receiving SLA-identical kidney grafts without CyA also showed stable serum creatinine levels and became tolerant. However, in neither of these animals could donor leukocytes be detected in the peripheral blood beyond 1 wk following transplantation. In one additional control animal, ureteral obstruction occurred at day 10, and was associated with additional peripheral chimerism, presumably related to inflammation rather than to immune status. These results indicate that the persistence of donor cell chimerism is not a requirement for the maintenance of tolerance to organ allografts in this model.
Triggering of Murine NK Cells by CD40 and CD86 (B7-2)
Authors: Martín-Fontecha Alfonso , Assarsson Erika , Carbone Ennio , Kärre Klas , Ljunggren Hans-Gustaf 
Published: January 2023

Abstract
NK cell-mediated cytotoxicity is regulated by both triggering and inhibitory signals. The interaction between MHC class I molecules expressed on target cells and specific MHC class I-binding receptors expressed by NK cells generally leads to inhibition of lysis. We have shown recently that CD80 (B7-1) in mice and CD40 in humans trigger NK cell-mediated cytotoxicity in vitro. In the present study, we show that murine CD40 and CD86 (B7-2) trigger murine NK cell-mediated cytotoxicity in vitro when expressed on tumor cells. Preincubation of the transfected cell lines with anti-CD40 F(ab′)2 fragments or cytolytic T lymphocyte-associated Ag-4-Ig (CTLA-4-Ig) before the cytotoxic assay abolished the triggering effect. Furthermore, radiolabeled CD40- and B7-2-expressing cells were rapidly eliminated in vivo in an NK cell-dependent manner. NK cells from CD40 ligand (CD40L)−/− or CD28−/− mice were triggered by tumor cells transfected with CD40 and B7-2, respectively, and these transfectants were rapidly eliminated in vivo when inoculated into CD40L−/− and CD28−/− mice. This suggests that the CD40 and B7-2 molecules can interact with receptors on NK cells other than CD40L and CD28, respectively, and that these may account for some of the reactivities observed in the present study. Collectively, these data demonstrate that 1) costimulatory molecules, other than B7-1, can modulate NK cell responses in vitro, 2) they can also affect NK cell-dependent responses in vivo, and 3) parts of these reactions are independent of CD28 and CD40L.
Mouse NKR-P1B, a Novel NK1.1 Antigen with Inhibitory Function
Authors: Carlyle James R. , Martin Alberto , Mehra Arun , Attisano Liliana , Tsui Florence W. , Zúñiga-Pflücker Juan Carlos 
Published: January 2023

AbstractThe mouse NK1.1 Ag originally defined as NK cell receptor (NKR)-P1C (CD161) mediates NK cell activation. Here, we show that another member of the mouse CD161 family, NKR-P1B, represents a novel NK1.1 Ag. In contrast to NKR-P1C, which functions as an activating receptor, NKR-P1B inhibits NK cell activation. Association of NKR-P1B with Src homology 2-containing protein tyrosine phosphatase-1 provides a molecular mechanism for this inhibition. The existence of these two NK1.1 Ags with opposite functions suggests a potential role for NKR-P1 molecules, such as those of the Ly-49 gene family, in regulating NK cell function.