bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-2-Mediated Cell Cycle Progression and Inhibition of Apoptosis Does Not Require NF-κB or Activating Protein-1 Activation in Primary Human T Cells
Authors: Iacobelli Milena , Rohwer Forest , Shanahan Paul , Quiroz Jose A. , McGuire Kathleen L. 
Published: January 2023

AbstractThe IL-2 growth hormone is the major growth factor of activated T lymphocytes during a developing immune response. IL-2 is required not only for cell cycle progression but also to protect Ag-activated T cells from programmed cell death. In several cell types, activation of NF-κB and/or activating protein-1 (AP-1) has been demonstrated to be extremely important in blocking apoptosis. To determine whether either or both of these transcription factors are involved in cell survival or cell cycle progression in response to IL-2, primary human T cells responsive to the growth factor were analyzed for NF-κB and AP-1 activation. The current study clearly demonstrates that IL-2 does not induce IκBα degradation or NF-κB activation in primary human T cells that respond to IL-2 by entering the cell cycle and avoiding apoptosis. Similarly, IL-2 neither activates JNK nor increases AP-1 binding activity to a consensus o-tetradecanoylphorbol 13-acetate (TPA) response element. On the other hand, the growth factor does induce the activation of STAT3 and STAT5 in these cells, as has been previously demonstrated. These data show that neither NF-κB nor AP-1 activation is required for IL-2-mediated survival or cell cycle progression in activated primary human T cells.
Suppressive Immunization with DNA Encoding a Self-Peptide Prevents Autoimmune Disease: Modulation of T Cell Costimulation
Authors: Ruiz Pedro J. , Garren Hideki , Ruiz Irene U. , Hirschberg David L. , Nguyen Louis-Vu T. , Karpuj Marcela V. , Cooper Minton T. , Mitchell Dennis J. , Fathman C. Garrison , Steinman Lawrence 
Published: January 2023

Abstract
Usually we rely on vaccination to promote an immune response to a pathogenic microbe. In this study, we demonstrate a suppressive form of vaccination, with DNA encoding a minigene for residues 139–151 of myelin proteolipid protein (PLP139–151), a pathogenic self-Ag. This suppressive vaccination attenuates a prototypic autoimmune disease, experimental autoimmune encephalomyelitis, which presents clinically with paralysis. Proliferative responses and production of the Th1 cytokines, IL-2 and IFN-γ, were reduced in T cells responsive to PLP139–151. In the brains of mice that were successfully vaccinated, mRNA for IL-2, IL-15, and IFN-γ were reduced. A mechanism underlying the reduction in severity and incidence of paralytic autoimmune disease and the reduction in Th1 cytokines involves altered costimulation of T cells; loading of APCs with DNA encoding PLP139–151 reduced the capacity of a T cell line reactive to PLP139–151 to proliferate even in the presence of exogenous CD28 costimulation. DNA immunization with the myelin minigene for PLP-altered expression of B7.1 (CD80), and B7.2 (CD86) on APCs in the spleen. Suppressive immunization against self-Ags encoded by DNA may be exploited to treat autoimmune diseases.
B Cell Maintenance in Aged Mice Reflects Both Increased B Cell Longevity and Decreased B Cell Generation
Authors: Kline Gregory H. , Hayden Tracy A. , Klinman Norman R. 
Published: January 2023

AbstractIn aged mice the population of mature peripheral B cells is maintained despite a severalfold decrease in the population of bone marrow B cell progenitors. The analysis of the rate of accumulation of 5′-bromo-2-deoxyuridine (BrdU)-labeled splenic B cells in mice fed BrdU for 8 days to 8 wk demonstrated a severalfold increase in the half-life of mature B cells in aged mice. Consistent with a role for decreased B cell turnover in maintaining the mature B cell population of aged mice, several findings indicate that fewer newly generated B cells enter the spleen from the bone marrow in aged vs young adult mice. These include 1) a fourfold decrease in the population of relatively immature splenic B cells, defined as cells that express high levels of heat-stable Ag and accumulate BrdU within 8 wk of labeling; and 2) an equivalent decrease in the population of bone marrow cells representative of later stages of B cell maturation (sIgD−sIgMint-high). Surprisingly, despite a four- to sixfold decrease in pre-B cells, the population of least mature bone marrow B cells (IgD−sIgMvery low) remains intact. Because this population accumulates BrdU-labeled cells more slowly in aged mice than in younger mice, and bone marrow B cells at more mature developmental stages are diminished, it appears that in aged mice B cell development beyond the sIgMvery low stage may be retarded and that cells, therefore, accumulate within this population.
Effect of Fever-Like Whole-Body Hyperthermia on Lymphocyte Spectrin Distribution, Protein Kinase C Activity, and Uropod Formation
Authors: Wang Xiang-Yang , Ostberg Julie R. , Repasky Elizabeth A. 
Published: January 2023

AbstractRegional inflammation and systemic fever are hallmarks of host immune responses to pathogenic stimuli. Although the thermal element of fever is thought to enhance the activity of immune effector cells, it is unclear what the precise role of increased body temperatures is on the activation state and effector functions of lymphocytes. We report here that mild, fever-like whole body hyperthermia (WBH) treatment of mice results in a distinct increase in the numbers of tissue lymphocytes with polarized spectrin cytoskeletons and uropods, as visualized in situ. WBH also induces a coincident reorganization of protein kinase C (PKC) isozymes and increased PKC activity within T cells. These hyperthermia-induced cellular alterations are nearly identical with the previously described effects of Ag- and mitogen-induced activation on lymphocyte spectrin and PKC. Immunoprecipitation studies combined with dual staining and protein overlay assays confirmed the association of PKCβ and PKCθ with spectrin following its reorganization. The receptor for activated C kinase-1 was also found to associate with the spectrin-based cytoskeleton. Furthermore, all these molecules (spectrin, PKCβ, PKCθ, and receptor for activated C kinase-1) cotranslocate to the uropod. Enhanced intracellular spectrin phosphorylation upon WBH treatment of lymphocytes was also found and could be blocked by the PKC inhibitor bisindolylmaleimide I (GF109203X). These data suggest that the thermal element of fever, as mimicked by these studies, can modulate critical steps in the signal transduction pathways necessary for effective lymphocyte activation and function. Further work is needed to determine the cellular target(s) that transduces the signaling pathway(s) induced by hyperthermia.
Normal Development in Porcine Thymus Grafts and Specific Tolerance of Human T Cells to Porcine Donor MHC
Authors: Nikolic Boris , Gardner Jason P. , Scadden David T. , Arn J. Scott , Sachs David H. , Sykes Megan 
Published: January 2023

Abstract
The induction of T cell tolerance is likely to play an essential role in successful xenotransplantation in humans. In this study, we show that porcine thymus grafts in immunodeficient mice support normal development of polyclonal, functional human T cells. These T cells were specifically tolerant to MHC Ags of the porcine thymus donor and responded to nondonor porcine xenoantigens and alloantigens. Exogenous IL-2 did not abolish tolerance, suggesting central clonal deletion rather than anergy as the likely tolerance mechanism. Our study suggests that the thymic transplantation approach to achieving tolerance with restoration of immunocompetence may be applicable to xenotransplantation of pig tissues to humans.
Differential Sensitivity of Distinct Chlamydia trachomatis Isolates to IFN-γ-Mediated Inhibition
Authors: Perry Linda L. , Su Hua , Feilzer Karen , Messer Ron , Hughes Scott , Whitmire William , Caldwell Harlan D. 
Published: January 2023

Abstract
Resistance to the mouse pneumonitis (MoPn) strain of Chlamydia trachomatis has been mapped to MHC class II-restricted, IL-12-dependent CD4+ T cells that secrete a type 1 profile of proinflammatory cytokines, which includes IFN-γ and TNF-α. The relative contribution of IFN-γ is controversial, however, due to variation in results presented by different laboratories. To determine whether C. trachomatis strain differences contributed to this apparent conflict, the relative resistance of IFN-γ-deficient mice to murine and human strains of C. trachomatis was compared. All human serovars were much more sensitive to the direct inhibitory actions of IFN-γ than the MoPn strain. Furthermore, genital clearance of human serovar D in the C57BL/6 mouse was mediated by class II-independent mechanisms that probably involved local production of IFN-γ by cells of the innate immune system. TNF-α also contributed indirectly to host resistance against all strains tested. The differential susceptibility of distinct C. trachomatis strains to effector cytokines such as IFN-γ could not have been predicted by interstrain biologic variation or by the profile of cytokines stimulated during infection. These findings indicate that strain variation should be considered in situations where related isolates of a given parasite produce conflicting data in models of infection and immunity. They also suggest that stimulation of mucosal IFN-γ activity is a relevant goal for a human chlamydial vaccine.
IFN-γ Up-Regulates the A2B Adenosine Receptor Expression in Macrophages: A Mechanism of Macrophage Deactivation
Authors: Xaus Jordi , Mirabet Maribel , Lloberas Jorge , Soler Concepció , Lluis Carme , Franco Rafael , Celada Antonio 
Published: January 2023

Abstract
Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A2B and A3 adenosine receptor subtypes. The presence of A2B receptors was confirmed by flow cytometry using specific Abs. The A2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A2B receptors, but not agonists for A1, A2A, or A3, lead to an increase in cAMP levels. IFN-γ up-regulates the surface protein and gene expression of the A2B adenosine receptor by induction of de novo synthesis. The up-regulation of A2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A2B receptors by adenosine or its analogues inhibits the IFN-γ-induced expression of MHC class II genes and also the IFN-γ-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A2B adenosine receptor expression induced by IFN-γ could be a feedback mechanism for macrophage deactivation.
Dynamic Association of L-Selectin with the Lymphocyte Cytoskeletal Matrix
Authors: Evans Sharon S. , Schleider David M. , Bowman Lori A. , Francis Michelle L. , Kansas Geoffrey S. , Black Jennifer D. 
Published: January 2023

AbstractL-selectin mediates lymphocyte extravasation into lymphoid tissues through binding to sialomucin-like receptors on the surface of high endothelial venules (HEV). This study examines the biochemical basis and regulation of interactions between L-selectin, an integral transmembrane protein, and the lymphocyte cytoskeleton. Using a detergent-based extraction procedure, constitutive associations between L-selectin and the insoluble cytoskeletal matrix could not be detected. However, engagement of the L-selectin lectin domain by Abs or by glycosylation-dependent cell adhesion molecule-1, an HEV-derived ligand for L-selectin, rapidly triggered redistribution of L-selectin to the detergent-insoluble cytoskeleton. L-selectin attachment to the cytoskeleton was not prevented by inhibitors of actin/microtubule polymerization (cytochalasin B, colchicine, or nocodozole) or serine/threonine and tyrosine kinase activity (staurosporine, calphostin C, or genistein), although L-selectin-mediated adhesion of human PBL was markedly suppressed by these agents. Exposure of human PBL or murine pre-B transfectants expressing full-length human L-selectin to fever-range hyperthermia also markedly increased L-selectin association with the cytoskeleton, directly correlating with enhanced L-selectin-mediated adhesion. In contrast, a deletion mutant of L-selectin lacking the COOH-terminal 11 amino acids failed to associate with the cytoskeletal matrix in response to Ab cross-linking or hyperthermia stimulation and did not support adhesion to HEV. These studies, when taken together with the previously demonstrated interaction between the L-selectin cytoplasmic domain and the cytoskeletal linker protein α-actinin, strongly implicate the actin-based cytoskeleton in dynamically controlling L-selectin adhesion.
Elimination of the Immunogenicity of Therapeutic Antibodies
Authors: Gilliland Lisa K. , Walsh Louise A. , Frewin Mark R. , Wise Matt P. , Tone Masahide , Hale Geoff , Kioussis Dimitris , Waldmann Herman 
Published: January 2023

AbstractThe immunogenicity of therapeutic Abs limits their long-term use. The processes of complementarity-determining region grafting, resurfacing, and hyperchimerization diminish mAb immunogenicity by reducing the number of foreign residues. However, this does not prevent anti-idiotypic and anti-allotypic responses following repeated administration of cell-binding Abs. Classical studies have demonstrated that monomeric human IgG is profoundly tolerogenic in a number of species. If cell-binding Abs could be converted into monomeric non-cell-binding tolerogens, then it should be possible to pretolerize patients to the therapeutic cell-binding form. We demonstrate that non-cell-binding minimal mutants of the anti-CD52 Ab CAMPATH-1H lose immunogenicity and can tolerize to the “wild-type” Ab in CD52-expressing transgenic mice. This finding could have utility in the long-term administration of therapeutic proteins to humans.
Cutting Edge: Receptor-Mediated Endocytosis of Heat Shock Proteins by Professional Antigen-Presenting Cells
Authors: Arnold-Schild Danièle , Hanau Daniel , Spehner Danièle , Schmid Claudia , Rammensee Hans-Georg , de la Salle Henri , Schild Hansjörg 
Published: January 2023

AbstractImmunization with heat shock proteins (HSPs) induces Ag-specific CTL responses. The specificity of the immune response is based on peptides associated with HSPs. To investigate how exogenous HSP/peptide complexes gain access to the MHC class I-restricted Ag presentation pathway, we incubated the monocytic cell line P388D1 and the dendritic cell line D2SC/1 with gold-labeled HSPs gp96 and HSC70. We show that HSPs bind specifically to the surface of these APCs and are internalized spontaneously by receptor-mediated endocytosis, demonstrating the existence of specific receptors for HSPs on these cells. In addition, we observe colocalization of internalized HSPs and surface MHC class I molecules in early and late endosomal structures. These findings provide possible explanations for the immunogenicity of HSP/peptide complexes and for the transfer of HSP-associated peptides onto MHC class I molecules.
Cutting Edge: A Test of the Dominant Negative Signal Model for TCR Antagonism
Authors: Daniels Mark A. , Schober Sonya L. , Hogquist Kristin A. , Jameson Stephen C. 
Published: January 2023

Abstract
The mechanism by which TCR antagonists interfere with T cell activation is unclear. One popular hypothesis is that incomplete early signaling events induced by these ligands dominantly inhibit the T cell’s ability to respond to a copresented agonist ligand. Here we test this “dominant negative” signal hypothesis by studying T cells expressing two distinct MHC class I-restricted TCRs (2C and OT-I). Although responses through each TCR can be efficiently inhibited by their specific antagonists, we found no evidence for “cross-antagonism” in which an antagonist for receptor “A” blocks responses through receptor “B.” Such inhibition would have been expected were the dominant negative signaling hypothesis correct, and alternative models for TCR antagonism are discussed.
Cutting Edge: SOCS-1 Is a Potent Inhibitor of IL-4 Signal Transduction
Authors: Losman J. A. , Chen X. P. , Hilton D. , Rothman P. 
Published: January 2023

AbstractIL-4 is an important regulator of the activation, proliferation, and differentiation of many hematopoetic cells. Many of these biological effects result from the activation of Janus kinases (JAK)1 and JAK3 and the transcription factor Stat6. Recent data suggest that members of the SOCS (suppressor of cytokine signaling) family of proteins can inhibit JAK-STAT signaling. We have examined the ability of SOCS family members to suppress IL-4 signaling, and we have found that SOCS-1 potently inhibits the activation of JAK1 kinase and Stat6 in response to IL-4. Furthermore, SOCS-1 can inhibit the induction of CD23 expression by IL-4. SOCS-2 does not inhibit induction of signaling by IL-4, while inhibition of IL-4 signaling by SOCS-3 can be detected in transient transfection systems, but not in stable cell lines. These studies implicate SOCS-1 in modulation of IL-4 signaling and suggest that SOCS-1 may play a role in regulating the immune response.
Survival of Naive CD4 T Cells: Roles of Restricting Versus Selecting MHC Class II and Cytokine Milieu
Authors: Boursalian Tamar E. , Bottomly Kim 
Published: January 2023

Abstract
The diversity of naive CD4 T cells plays an important role in the adaptive immune response by ensuring the capability of responding to novel pathogens. In the past, it has been generally accepted that naive CD4 T cells are intrinsically long-lived; however, there have been studies suggesting some CD4 T cells are short-lived. In this report, we identify two populations of naive CD4 T cells: a long-lived population as well as a short-lived population. In addition, we identify two factors that contribute to the establishment of long-lived naive CD4 T cells. We confirm earlier findings that MHC class II interaction with the TCR on CD4 T cells is important for survival. Furthermore, we find that MHC class II alleles with the correct restriction element for Ag presentation mediate the peripheral survival of naive CD4 T cells more efficiently than other positively selecting alleles, regardless of the selecting MHC in the thymus. The second component contributing to the survival of naive CD4 T cells is contact with the cytokines IL-4 and IL-7. We find that the physiological levels of IL-4 and IL-7 serve to enhance the MHC class II-mediated survival of naive CD4 T cells in vivo.
Factors Regulating Stem Cell Recruitment to the Fetal Thymus
Authors: Wilkinson B. , Owen J. J. T. , Jenkinson E. J. 
Published: January 2023

Abstract
Colonization of the thymic rudiment during development is initiated before vascularization so that hemopoietic precursors must leave the pharyngeal vessels and migrate through the perithymic mesenchyme to reach the thymus, suggesting that they may be responding to a gradient of chemoattractant factors. We report that diffusible chemoattractants are produced by MHC class II+ epithelial cells of the fetal thymus, and that the response of precursors to these factors is mediated via a G protein-coupled receptor, consistent with factors being members of the chemokine family. Indeed, a number of chemokine receptors are expressed by thymic precursors, and several chemokines are also expressed by thymic epithelial cells. However, these chemokines are also expressed in a tissue that is unable to attract precursors, although the thymus expressed chemokine, TECK, is expressed at higher levels in thymic epithelial cells and we show that it has chemotactic activity for isolated thymic precursors. Neutralizing Ab to TECK, however, did not prevent thymus recolonization by T cell precursors, suggesting that other novel chemokines might be involved in this process. In addition, we provide evidence for the involvement of matrix metalloproteinases in chemoattractant-mediated T cell precursor recruitment to the thymus during embryogenesis.
Cross-Recognition of Two Middle T Protein Epitopes by Immunodominant Polyoma Virus-Specific CTL
Authors: Wilson Christopher S. , Moser Janice M. , Altman John D. , Jensen Peter E. , Lukacher Aron E. 
Published: January 2023

AbstractWe recently identified the immunodominant epitope for polyoma virus-specific CTL as the Dk-associated peptide MT389–397 derived from the middle T (MT) viral oncoprotein. Another Dk-restricted peptide corresponding to residues 236–244 of MT was recognized by nearly all MT389–397-reactive CTL clones, but required concentrations at least 2 logs higher to sensitize syngeneic target cells for lysis. Except for identity at the three putative Dk-peptide anchor residues, MT236–244 shares no homology with MT389–397. Using a novel europium-based class I MHC-peptide binding immunoassay, we determined that MT236–244 bound Dk 2–3 logs less well than MT389–397. Infection with a mutant polyoma virus whose MT is truncated just before the MT389–397 epitope or immunization with MT389–397 or MT236–244 peptides elicited CTL that recognized both MT389–397 and MT236–244. Importantly, infection with a polyoma virus lacking MT389–397 and mutated in an MT236–244 Dk anchor position induced polyoma virus-specific CTL recognizing neither MT389–397 nor MT236–244 epitopes. Despite predominant usage of the Vβ6 gene segment, MT389–397/MT236–244 cross-reactive CTL clones possess diverse complementarity-determining region 3β domains; this is functionally reflected in their heterogeneous recognition patterns of alanine-monosubstituted MT389–397 peptides. Using Dk/MT389–397 tetramers, we directly visualized MT236–244 peptide-induced TCR down-modulation of virtually all MT389–397-specific CD8+ T cells freshly explanted from polyoma-infected mice, suggesting that a single TCR recognizes both Dk-restricted epitopes. The availability of immunodominant epitope-specific CTL capable of recognizing a second epitope in MT, a viral protein essential for tumorigenesis, may serve to amplify the CTL response to the immunodominant epitope and prevent the emergence of immunodominant epitope-loss viruses and virus-induced tumors.
Adjuvant-Guided Type-1 and Type-2 Immunity: Infectious/Noninfectious Dichotomy Defines the Class of Response
Authors: Yip Hualin C. , Karulin Alexey Y. , Tary-Lehmann Magdalena , Hesse Maike D. , Radeke Heinfried , Heeger Peter S. , Trezza Richard P. , Heinzel Frederick P. , Forsthuber Thomas , Lehmann Paul V. 
Published: January 2023

AbstractTraditionally, protein Ags have been injected in CFA (oil with inactivated mycobacteria) to induce immunity and with IFA (oil alone) to induce tolerance. We report here that injection of hen eggwhite lysozyme, a prototypic Ag, in CFA-induced and IFA-induced pools of hen eggwhite lysozyme-specific memory T cells of comparable fine specificity, clonal size, and avidity spectrum, but with type-1 and type-2 cytokine signatures, respectively. This adjuvant-guided induction of virtually unipolar type-1 and type-2 immunity was observed with seven protein Ags and in a total of six mouse strains. Highly polarized type-1 and type-2 immunity are thus readily achievable through the choice of adjuvant, irrespective of the genetic bias of the host and of the nature of the protein Ag. This finding should have far-reaching implications for the development of vaccines against infectious and autoimmune diseases. Furthermore, our demonstration that Ag injected with IFA is as strongly immunogenic for T cells as it is with CFA shows that the presence of the mycobacteria determines not the priming of naive T cells through the second-signal link but the path of downstream differentiation toward CD4 memory cells that express either type-1 or type-2 cytokines.