bluuebunny/crossref_metadata_2025_split huggingface dataset:
Orally Induced Peripheral Nonresponsiveness Is Maintained in the Absence of Functional Th1 or Th2 Cells
Authors: Shi Hai Ning , Grusby Michael J. , Nagler-Anderson Cathryn 
Published: December 2022

AbstractIntragastric administration of soluble protein Ags results in peripheral tolerance to the fed Ag. To examine the role of cytokine regulation in the induction of oral tolerance, we fed OVA to mice deficient in Th1 (Stat 4−/−) and Th2 (Stat 6−/−) cells and compared their response to that of normal BALB/c controls. We found that, in spite of these deficiencies, OVA-specific peripheral cell-mediated and humoral nonresponsiveness was maintained in both Stat 4−/− and Stat 6−/− mice. In the mucosa, both Peyer’s patch T cell proliferative responses and OVA-specific fecal IgA were reduced in Stat 4−/− and Stat 6−/− mice fed OVA but not in normal BALB/c controls. Mucosal, but not peripheral, nonresponsiveness was abrogated by the inclusion of a neutralizing Ab to TGF-β in the culture medium. Our results show that, in the periphery, tolerance to oral Ag can be induced in both a Th1- or Th2-deficient environment. In the mucosa, however, the absence of Th1 and Th2 cytokines can markedly affect this response, perhaps by regulation of TGF-β-secreting cells.
Signaling Through CD5 Involves Acidic Sphingomyelinase, Protein Kinase C-ζ, Mitogen-Activated Protein Kinase Kinase, and c-Jun NH2-Terminal Kinase
Authors: Simarro María , Calvo Javier , Vilà Josep M. , Places Lourdes , Padilla Olga , Alberola-Ila José , Vives Jordi , Lozano Francisco 
Published: December 2022

AbstractThe CD5 lymphocyte surface glycoprotein is a coreceptor involved in the modulation of Ag-specific receptor-mediated activation and differentiation signals. The molecular basis for its modulatory properties is not yet well understood. In the present study we describe early biochemical events triggered by CD5 stimulation, which include the phosphatidylcholine-specific phospholipase C (PC-PLC)-dependent activation of acidic sphingomyelinase (A-SMase) in normal and lymphoblastoid T and B cells. The functional coupling of PC-PLC and A-SMase is demonstrated by the abrogation of A-SMase activation by 1) xanthogenate tricyclodecan-9-yl (D609), a selective inhibitor of PC-PLC, and 2) replacement of several C-terminal serine residues (S458, S459, and S461) present in the cytoplasmic tail of CD5 that are known to be critical for PC-PLC activation. Additionally, we demonstrate that activation of protein kinase C-ζ (PKC-ζ) and members of the mitogen-activated protein kinase (MAPK) cascade (MAPK kinase and c-Jun NH2-terminal kinase), but not the NF-κB, are downstream events of the CD5 signaling pathway. A-SMase, PKC-ζ, and MAPK family members are key mediators of cell responses as diverse as proliferation, differentiation, and growth arrest and may contribute to CD5-mediated modulation of TCR or BCR signaling.
Splenic NK1.1-Negative, TCRαβ Intermediate CD4+ T Cells Exist in Naive NK1.1 Allelic Positive and Negative Mice, with the Capacity to Rapidly Secrete Large Amounts of IL-4 and IFN-γ Upon Primary TCR Stimulation
Authors: Moodycliffe Angus M. , Maiti Sourindra , Ullrich Stephen E. 
Published: December 2022

AbstractSplenic NK1.1+CD4+ T cells that express intermediate levels of TCRαβ molecules (TCRint) and the DX5 Ag (believed to identify an equivalent population in NK1.1 allelic negative mice) possess the ability to rapidly produce high quantities of immunomodulatory cytokines, notably IL-4 and IFN-γ, upon primary TCR activation in vivo. Indeed, only T cells expressing the NK1.1 Ag appear to be capable of this function. In this study, we demonstrate that splenic NK1.1-negative TCRintCD4+ T cells, identified on the basis of FcγR expression, exist in naive NK1.1 allelic positive (C57BL/6) and negative (C3H/HeN) mice with the capacity to produce large amounts of IL-4 and IFN-γ after only 8 h of primary CD3 stimulation in vitro. Furthermore, a comparison of the amounts of early cytokines produced by FcγR+CD4+TCRint T cells with NK1.1+CD4+ or DX5+CD4+TCRint T cells, simultaneously isolated from C57BL/6 or C3H/HeN mice, revealed strain and population differences. Thus, FcγR defines another subpopulation of splenic CD4+TCRint cells that can rapidly produce large concentrations of immunomodulatory cytokines, suggesting that CD4+TCRint T cells themselves may represent a unique family of immunoregulatory CD4+ T cells whose members include FcγR+CD4+ and NK1.1/DX5+CD4+ T cells.
Distribution of Cycling T Lymphocytes in Blood and Lymphoid Organs During Immune Responses
Authors: Vasseur Florence , Le Campion Armelle , Pavlovitch Jana H. , Pénit Claude 
Published: December 2022

Abstract
Proliferation of murine T lymphocytes in blood, lymph nodes, and spleen was studied in four in vivo stimulation systems, using BrdU pulse-labeling of DNA-synthesizing cells. The T cell response to the superantigen Staphylococcus enterotoxin B (SEB) was studied in detail. Vβ8+ T cells showed a peak of DNA synthesis 16–24 h after SEB injection, and the percentage of BrdU+ CD4 and CD8 T cells was higher in blood than in lymph nodes and spleen. DNA synthesis was preceded by massive migration of Vβ8+ cells from blood to lymphoid organs, in which the early activation marker CD69 was first up-regulated. SEB-nonspecific Vβ6+ cells showed minimal stimulation but, when cycling, also expressed a high level of CD69. The other systems studied were injection of the IFN-γ inducer polyinosinic:polycytidylic acid, infection by the BM5 variants of murine leukemia virus (the causative agent of murine AIDS), and T cell expansion after transfer of normal bone marrow and lymph node cells into recombinase-activating gene-2-deficient mice. In each case, a peak of T cell proliferation was observed in blood. These data demonstrate the extensive redistribution of cycling T cells in the first few hours after activation. Kinetic studies of blood lymphocyte status appear crucial for understanding primary immune responses because cycling and redistributing T lymphocytes are enriched in the circulating compartment.
Human CD4+ T Cells Mediate Rejection of Porcine Xenografts
Authors: Friedman Tony , Shimizu Akira , Smith Rex Neal , Colvin Robert B. , Seebach Jörg D. , Sachs David H. , Iacomini John 
Published: December 2022

AbstractIt has previously been demonstrated that xenograft rejection in rodents is dependent on CD4+ T cells. However, because of the lack of an appropriate in vivo model, little is known about the cellular basis of human T cell-mediated rejection of xenografts. In this study, we have evaluated the ability of human T cells to mediate rejection of porcine skin grafts in a novel in vivo experimental system using immunodeficient mice as recipients. Recombinase-activating gene-1-deficient mice (R−) lacking mature B and T cells were grafted with porcine skin and received human lymphocytes stimulated in vitro with irradiated porcine PBMC. Skin grafts on mice given either unseparated, activated human lymphocytes, or NK cell-depleted lymphocyte populations were rejected within 18 days after adoptive cell transfer. In contrast, skin grafts on mice given T cell-depleted human lymphocytes or saline showed no gross or histologic evidence of rejection up to 100 days after adoptive transfer. Purified CD4+ T cells were also able to mediate rejection of porcine skin grafts. These data suggest that human CD4+ T cells are sufficient to induce rejection of porcine xenografts. Thus, strategies directed toward CD4+ T cells may effectively prevent cellular rejection of porcine xenografts in humans.
Virus and Autoimmunity: Induction of Autoimmune Disease in Mice by Mouse T Lymphotropic Virus (MTLV) Destroying CD4+ T Cells
Authors: Morse Stephen S. , Sakaguchi Noriko , Sakaguchi Shimon 
Published: December 2022

AbstractNeonatal infection of the mouse T lymphotropic virus (MTLV), a member of herpes viridae, causes various organ-specific autoimmune diseases, such as autoimmune gastritis, in selected strains of normal mice. The infection selectively depletes CD4+ T cells in the thymus and periphery for 2–3 wk from 1 wk after infection. Thymectomy 3 wk after neonatal MTLV infection enhances the autoimmune responses and produces autoimmune diseases at higher incidences and in a wider spectrum of organs than MTLV infection alone. On the other hand, inoculation of peripheral CD4+ cells from syngeneic noninfected adult mice prevents the autoimmune development. These autoimmune diseases can be adoptively transferred to syngeneic athymic nude mice by CD4+ T cells. The virus is not detected by bioassay in the organs/tissues damaged by the autoimmune responses. Furthermore, similar autoimmune diseases can be induced in normal mice by manipulating the neonatal thymus/T cells (e.g., by neonatal thymectomy) without virus infection. These results taken together indicate that neonatal MTLV infection elicits autoimmune disease by primarily affecting thymocytes/T cells, not self Ags. It may provoke or enhance thymic production of CD4+ pathogenic self-reactive T cells by altering the thymic clonal deletion mechanism, or reduce the production of CD4+ regulatory T cells controlling self-reactive T cells, or both. The possibility is discussed that other T cell-tropic viruses may cause autoimmunity in humans and animals by affecting the T cell immune system, not the self Ags to be targeted by the autoimmunity.
Bcl-2-Induced Changes in E2F Regulatory Complexes Reveal the Potential for Integrated Cell Cycle and Cell Death Functions
Authors: Lind Evan F. , Wayne Jay , Wang Qi-Zhi , Staeva Teodora , Stolzer Amy , Petrie Howard T. 
Published: December 2022

Abstract
Proliferation and cell death are tightly linked fates during cell and tissue differentiation. In the past few years, it has been shown that Bcl-2 exhibits a potent cell cycle inhibitory effect, in addition to its better known role in the antagonism of cell death. In the present study, we show that the cell cycle effects of Bcl-2 apparently occur at the level of E2F control of gene transcription. Under conditions of normal cell growth, or under conditions that lead to cell death in the absence of Bcl-2, bcl-2 expression results in a reduction of free (active) E2F isoforms and in an increase in the formation of higher-order (inactive) complexes. Bcl-2-induced changes in E2F complex formation are paralleled by an apparent increase in pRb regulatory activity, by the up-regulation of p130 protein expression, and by the formation of E2F/p130 complexes at the expense of those consisting of E2F/p107. Cells lacking bcl-2 expression respond to growth factor withdrawal in the opposite manner, by the liberation of E2F from inactivating complexes and by continued cell cycle leading to cell death. These analyses reveal a mechanism for cell cycle regulation by Bcl-2 that occurs at the level of E2F transcriptional activity. Further, since specific E2F activities are clearly linked to the induction of cell death, these findings may help to consolidate the cell survival and cell cycle effects of Bcl-2 through a common transcriptional mechanism.
In Vitro Induction of the Expression of Multiple IgA Isotype Genes in Rabbit B Cells by TGF-β and IL-2
Authors: Spieker-Polet Helga , Yam Pi-Chen , Arbieva Zarema , Zhai Shi-Kang , Knight Katherine L. 
Published: December 2022

AbstractThe rabbit genome has 13 different Cα genes that are expressed at different levels in mucosal tissues. To analyze the factors involved in the differential expression of these Cα genes, we cloned and sequenced the promoters of the Iα regions that control the expression of sterile mRNA. We found that all Cα genes, including Cα3 and Cα8, which are not expressed, and Cα4, which is expressed at high levels, have similar nucleotide sequences in the Iα region, and all contain the recognition elements for TGF-β in the promoter. B lymphocytes from popliteal lymph nodes or Peyer’s patch activated in vitro could be induced by TGF-β to express sterile IgA transcripts of all IgA isotypes, except Cα2, Cα3, and Cα8. Many single B lymphocytes transcribed sterile mRNA of more than one IgA isotype, which demonstrates that transcription of sterile mRNA alone does not regulate the IgA isotype switch. The addition of IL-2 led to the expression of transcripts of mature IgA of all isotypes, except Cα2, Cα3, and Cα8. The predominantly expressed isotype in these experiments was Cα4. With the use of an IgA4-specific mAb we found that IgA4+ plasma cells are unevenly distributed throughout the small intestine such that many of the IgA+ plasma cells in the duodenum-jejunum produced IgA4, whereas in the lower part of the ileum IgA4-producing cells were almost absent. Because the microbial flora varies throughout the intestine, we suggest that the microbial flora creates different local environments and thus affects either isotype switching or homing of IgA-expressing cells.
Down-Regulation of CXCR4 by Human Herpesvirus 6 (HHV-6) and HHV-7
Authors: Yasukawa Masaki , Hasegawa Atsuhiko , Sakai Ikuya , Ohminami Hideki , Arai Junko , Kaneko Shin , Yakushijin Yoshihiro , Maeyama Kazutaka , Nakashima Hideki , Arakaki Rieko , Fujita Shigeru 
Published: December 2022

AbstractRecent studies have demonstrated that human herpesvirus 6 (HHV-6) and HHV-7 interact with HIV-1 and alter the expression of various surface molecules and functions of T lymphocytes. The present study was undertaken to clarify whether coreceptors for HIV-1, CXCR4 and CCR5, are necessary for HHV-6 and HHV-7 infection. Although CXCR4 and CCR5 appeared not to be the coreceptors for these viruses, marked down-regulation of CXCR4, but not CCR5, was detected in HHV-6 variant A (HHV-6A)-, HHV-6 variant B (HHV-6B)-, and HHV-7-infected cells. Down-regulation of CXCR4 resulted in impairment of chemotaxis and a decreased level of elevation of the intracellular Ca2+ concentration in response to stromal cell-derived factor-1. Northern blot analysis of mRNAs extracted from HHV-6A-, HHV-6B-, and HHV-7-infected CD4+ T lymphocytes demonstrated a markedly decreased level of CXCR4 gene transcription, but the posttranscriptional stability of CXCR4 mRNA was not significantly altered. These data demonstrate that unlike HIV-1, HHV-6 and HHV-7 infections do not require expression of CXCR4 or CCR5, whereas marked down-regulation of CXCR4 is induced by these viruses, suggesting that HHV-6 and HHV-7 infections may render CD4+ T lymphocytes resistant to T lymphocyte-tropic HIV-1 infection.
Class II MHC/Peptide Complexes Are Released from APC and Are Acquired by T Cell Responders During Specific Antigen Recognition
Authors: Patel Dhaval M. , Arnold Paula Y. , White Gregory A. , Nardella John P. , Mannie Mark D. 
Published: December 2022

AbstractT cell expression of class II MHC/peptide complexes may be important for maintenance of peripheral self-tolerance, but mechanisms underlying the genesis of class II MHC glycoproteins on T cells are not well resolved. T cell APC (T-APC) used herein were transformed IL-2-dependent clones that constitutively synthesized class II MHC glycoproteins. When pulsed with myelin basic protein (MBP) and injected into Lewis rats, these T-APC reduced the severity of experimental autoimmune encephalomyelitis, whereas unpulsed T-APC were without activity. Normal MBP-reactive clones cultured without APC did not express class II MHC even when activated with mitogens and exposed to IFN-γ. However, during a 4-h culture with T-APC or macrophage APC, recognition of MBP or mitogenic activation of responder T cells elicited high levels of I-A and I-E expression on responders. Acquisition of class II MHC glycoproteins by responders was resistant to the protein synthesis inhibitor cycloheximide, coincided with transfer of a PKH26 lipophilic dye from APC to responders, and resulted in the expression of syngeneic and allogeneic MHC glycoproteins on responders. Unlike rested I-A− T cell clones, rat thymic and splenic T cells expressed readily detectable levels of class II MHC glycoproteins. When preactivated with mitogens, naive T cells acquired APC-derived MHC class II molecules and other membrane-associated proteins when cultured with xenogeneic APC in the absence of Ag. In conclusion, this study provides evidence that APC donate membrane-bound peptide/MHC complexes to Ag-specific T cell responders by a mechanism associated with the induction of tolerance.
Primary Peripheral Blood Eosinophils Rapidly Degrade Transfected Granulocyte-Macrophage Colony-Stimulating Factor mRNA
Authors: Esnault Stéphane , Malter James S. 
Published: December 2022

AbstractDespite increasing interest, very little information exists regarding gene regulatory mechanisms employed by eosinophils. This largely stems from the difficulty in transfecting these primary cells. In this study, we demonstrate that peripheral blood eosinophils (PBEos) can be successfully transfected with both GM-CSF cDNA and mRNA and reporter constructs by particle-mediated gene transfer. The transfection efficiency was 1.2% based on green fluorescent protein-positive cells. Promoter studies revealed CMV-driven expression vectors were initially active but rapidly quenched, while viral long terminal repeats had greater activity, indicating that certain viral constructs may be relatively poor to direct the production of transgenic proteins in PBEos. Exogenous GM-CSF mRNA was readily delivered and detected by Northern blot, permitting determination of its t1/2 in the absence of transcriptional poisons. These data show PBEos rapidly degraded GM-CSF mRNA with a t1/2 of 8 min. Mutant GM-CSF mRNAs, lacking the AUUUA motifs, were more stable, but were still rapidly degraded, suggesting the existence of accessory, destabilizing elements. We were able to measure minute amounts of intracellular GM-CSF after the transfection of mutant GM-CSF mRNA, but extracellular cytokine was below the sensitivity of our ELISA. However, the presence of secreted GM-CSF was established by in vitro, survival bioassay. In conclusion, the existence of this new technology should allow detailed studies of eosinophil-specific transcriptional and posttranscriptional regulation.
Lad, an Adapter Protein Interacting with the SH2 Domain of p56lck, Is Required for T Cell Activation
Authors: Choi Young Bong , Kim Chan Ki , Yun Yungdae 
Published: December 2022

Abstract
T cell-specific Src family tyrosine kinase, p56lck, plays crucial roles in T cell differentiation, activation, and proliferation. These multiple functions of p56lck are believed to be conducted through the protein-protein interactions with various cellular signaling proteins. To clarify the mechanisms through which p56lck contributes to T cell signaling, we identified the proteins binding to the Src homology 2 (SH2) domain of p56lck through a tyrosine phosphorylation-dependent yeast two-hybrid screening. Subsequent characterization of positive clones revealed the presence of a protein of 366 aa named Lad (Lck-associated adapter protein), which is a potential murine homologue of previously reported TSAd, a T cell-specific adapter protein. Lad contains several protein-protein interaction domains including a zinc-finger motif, an SH2 domain, a proline-rich SH3 binding motif, and several phosphotyrosine sites. Furthermore, Lad was tyrosine phosphorylated and associated with p56lckin vivo and redistributed from cytoplasm to the plasma membrane in a T cell activation-dependent manner. Moreover in T cells, IL-2 promoter activity was enhanced upon coexpression of Lad but was inhibited by the coexpression of antisense Lad RNA. These characteristics of Lad suggest that Lad play an essential role as an adapter protein in p56lck-mediated T cell signaling.
CD4+ T Cell Responses to CD40-Deficient APCs: Defects in Proliferation and Negative Selection Apply Only with B Cells as APCs
Authors: Ozaki Minette E. , Coren Barbara A. , Huynh Tracy N. , Redondo Deborah J. , Kikutani Hitoshi , Webb Susan R. 
Published: December 2022

AbstractDuring T-APC interactions in vivo, interfering with CD40-CD154 interactions leads to reduced T cell priming, defects in effector function, and, in some cases, T cell tolerance. As shown here, however, presentation of conventional peptide Ags by CD40-deficient spleen APC in vitro leads to normal CD4+ T cell proliferative responses. By contrast, responses to the same peptides presented by purified B cells were markedly reduced in the absence of CD40. Thus, the requirement for CD40-CD154 interactions appears to be strongly influenced by the type of APC involved. Analysis of responses to endogenous superantigens, which are known to be strongly dependent on B cells for presentation, indicated that CD4+ responses to strong Ags are less dependent on CD40 than are responses to weak Ags. Similar findings applied to negative selection in the thymus. Thus, deletion of potentially autoreactive cells depended on CD40 expression when B APC were involved, and this requirement was most pronounced when negative selection was directed to weak Ags.
Autoimmune Myocarditis Does Not Require B Cells for Antigen Presentation
Authors: Malkiel Susan , Factor Stephen , Diamond Betty 
Published: December 2022

AbstractT cells constitute the pathogenic effector cell population in autoimmune myocarditis in BALB/c mice. Using mice rendered deficient for B cells by a targeted disruption to the IgM transmembrane domain or by treatment with anti-IgM Ab from birth, we asked whether B cells are a critical APC in the induction of autoimmune myocarditis. B cell-deficient mice immunized with cardiac myosin develop myocarditis comparable in incidence and severity to that in wild-type mice, suggesting that autoreactive T cells that cause myocarditis in BALB/c mice are activated by macrophages or dendritic cells. Since it does not appear that presentation of cryptic epitopes is critical for the breakdown of self tolerance, potentially pathogenic T cells recognizing dominant myosin epitopes must have escaped tolerization. Either anatomic sequestration of cardiac myosin peptide-MHC complexes or subthreshold presentation of cardiac myosin peptides by conventional APC can explain the survival of these autoreactive T cells.
Structure/Function Relationship of Activating Ly-49D and Inhibitory Ly-49G2 NK Receptors
Authors: Ortaldo John R. , Winkler-Pickett Robin , Willette-Brown Jami , Wange Ronald L. , Anderson Stephen K. , Palumbo Gregory J. , Mason Llewellyn H. , McVicar Daniel W. 
Published: December 2022

AbstractMurine NK cells express Ly-49 family receptors capable of either inhibiting or activating lytic function. The overlapping patterns of expression of the various receptors have complicated their precise biochemical characterization. Here we describe the use of the Jurkat T cell line as the model for the study of Ly-49s. We demonstrate that Ly-49D is capable of delivering activation signals to Jurkat T cells even in the absence of the recently described Ly-49D-associated chain, DAP-12. Ly-49D signaling in Jurkat leads to tyrosine phosphorylation of TCRζ and requires Syk/Zap70 family kinases and arginine 54 of Ly-49D, suggesting that Ly-49D signals via association with TCRζ. Coexpression studies in 293-T cells confirmed the ability of Ly-49D to associate with TCRζ. In addition, we have used this model to study the functional interactions between an inhibitory Ly-49 (Ly-49G2) and an activating Ly-49 (Ly-49D). Ly-49G2 blocks activation mediated by Ly-49D in an immunoreceptor tyrosine-based inhibitory motif (ITIM)-dependent manner. In contrast, Ly-49G2 was incapable of inhibiting activation by the TCR even though human killer cell inhibitory receptor (KIR) (KIR3DL2(GL183)) effectively inhibits TCR. Both the ability of Ly-49G2 to block Ly-49D activation and the failure of Ly-49G2 to inhibit TCR signaling were confirmed in primary murine NK cells and NK/T cells, respectively. These data demonstrate the dominant effects of the inhibitory receptors over those that activate and suggest an inability of the Ly-49 type II inhibitory receptors to efficiently inhibit type I transmembrane receptor signaling in T cells and NK cells.