bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation by Thyroid Hormone of Human IFN-γ-Induced HLA-DR Expression
Authors: Lin Hung-Yun , Martino Leon J. , Wilcox Brian D. , Davis Faith B. , Gordinier Jennifer K. , Davis Paul J. 
Published: December 2022

Abstract
We have investigated the mechanism by which thyroid hormone potentiates IFN-γ-induced HLA-DR expression. IFN-γ-induced HLA-DR expression requires activation of STAT1α and induction of the Class II trans-activator, CIITA. HeLa and CV-1 cells treated only with l-thyroxine (T4) demonstrated increased tyrosine phosphorylation and nuclear translocation (= activation) of STAT1α; this hormone effect on signal transduction, and T4 potentiation of IFN-γ-induced HLA-DR expression, were blocked by the inhibitors CGP 41251 (PKC) and genistein (tyrosine kinase). Treatment of cells with T4-agarose also caused activation of STAT1α. In the presence of IFN-γ, T4 enhanced cytokine-induced STAT1α activation. Potentiation by T4 of IFN-γ action was associated with increased mRNA for both CIITA and HLA-DR, with peak enhancement at 16 h (CIITA), and 2 d (HLA-DR). T4 increased IFN-γ-induced HLA-DR protein 2.2-fold and HLA-DR mRNA fourfold after 2 d. Treatment with actinomycin D after induction of HLA-DR mRNA with IFN-γ, with or without T4, showed that thyroid hormone decreased the t1/2 of mRNA from 2.4 to 1.1 h. HeLa and CV-1 cells lack functional nuclear thyroid hormone receptor. Tetraiodothyroacetic acid (tetrac) and 3,5,3′-triiodo-thyroacetic acid (triac) blocked T4 potentiation of IFN-γ-induced HLA-DR expression and T4 activation of STAT1α. These studies define an early hormone recognition step at the cell surface that is novel, distinct from nuclear thyroid hormone receptor, and blocked by tetrac and triac. Thus, thyroid hormone potentiation of IFN-γ-induced HLA-DR transcription is mediated by a cell membrane hormone binding site, enhanced activation of STAT1α, and increased CIITA induction.
Regulation of Apoptosis by Tyrosine-Containing Domains of IL-4Rα: Y497 and Y713, But Not the STAT6-Docking Tyrosines, Signal Protection from Apoptosis
Authors: Zamorano José , Keegan Achsah D. 
Published: December 2022

AbstractIL-4 is a cytokine with important antiapoptotic activity. We have analyzed the role that tyrosine-containing domains within the cytoplasmic tail of IL-4Rα play in IL-4-mediated protection from apoptosis. 32D cells expressing a wt huIL-4Rα or one truncated at aa 557 were protected by huIL-4 from apoptosis while cells expressing a receptor truncated at aa 657 were not, suggesting that the carboxyl-terminal domain signals protection from apoptosis. However, changing Y713 within this region to phenylalanine had no effect. To analyze the contribution of tyrosine-containing domains independently, we transplanted regions of the huIL-4Rα to a truncated form of the huIL-2Rβ that could not signal protection from apoptosis. Transplantation of the huIL-4Rα domains containing Y497 or Y713 partially prevented cell death and together signaled protection from apoptosis in response to IL-2 as well as the wt IL-2Rβ. Mutation of Y497 and Y713 to phenylalanine inhibited protection. In contrast, transplantation of the domain containing the potential STAT6-docking tyrosines alone had no effect, yet it inhibited the protection mediated by the other domains. Although IL-4Rα signals Shc and SH2-containing inositol phosphatase (SHIP) phosphorylation, we could not establish an association between their activation and protection from apoptosis. Taken together, this study suggests that the domains of the huIL-4Rα containing Y497 and Y713 positively regulate protection from apoptosis while the domain containing the STAT6 docking sites suppresses this protection, and that additional signaling molecules other than insulin receptor substrate-1 (IRS1), Shc, or SHIP may be involved in antiapoptotic signaling.
Cutting Edge: Induction of Antigen-Specific Hyporesponsiveness by Transplantation of Hemopoietic Cells Containing an MHC Class I Transgene Regulated by a Lymphocyte-Specific Promoter
Authors: Hansal Susan A. , Morris Diane I. , Sechler Joan M. G. , Love Paul E. , Rosenberg Amy S. 
Published: December 2022

Abstract
We explored a novel approach to tolerance induction by the transplantation of bone marrow (BM) cells (BMCs) that themselves do not express a foreign histocompatibility Ag, but which give rise to mature lymphocytes that do so. Lines of transgenic (FVB) mice were generated that contained an MHC class I Dd cDNA regulated by a CD2 promoter. Because the CD2 promoter is lymphocyte-specific and activated relatively late in lymphocyte ontogeny, Dd is expressed on most mature lymphocytes in the periphery but only on developing B cells in the BM of transgenic mice. Transgenic BMCs are tolerogenic and reproducibly engraft in nontransgenic mice using a conditioning regimen that is nonpermissive for the engraftment of conventional (MHC promoter) Dd-transgenic BMCs. Engrafted BMCs generate transgene-expressing lymphocytes and confer a state of Ag-specific hyporesponsiveness on the host that is primarily attributable to a peripheral mechanism. The strategies by which tolerance can be optimized in this system are discussed.
Novel Diversity in Th1, Th2 Type Differentiation of Hemagglutinin-Specific T Cell Clones Elicited by Natural Influenza Virus Infection in Three Major Haplotypes (H-2b,d,k)
Authors: Graham Christine M. , Smith Claire A. , Thomas D. Brian 
Published: December 2022

AbstractWe report novel diversity in the lymphokine (LK) secretion profile of hemagglutinin-specific, CD4+ T cell clones elicited by influenza virus infection in three major haplotypes: I-Ad- or I-Ed-restricted T cell clones obtained from individual BALB/c donors, and specific for three distinct antigenic peptides (p56–76, or p186–205 or p177–199), were uniformly Th1 type, releasing only IFN-γ on activation. In contrast, extensive diversity was evident for the C57BL/10 or CBA/Ca repertoire. Sibling T cell clones, established from the same C57BL/10 donor and expressing identical TCR β-chains in their recognition of p186–205, released either (IFN-γ and IL-5) or (IFN-γ and IL-4 and IL-5) or (IL-4 and IL-5 and IL-10) following Ag-specific or nonspecific stimulation. Similarly, I-Ak-restricted T cell clones, specific for p120–139 secreted either (IFN-γ only) or (IFN-γ and IL-5) or (IFN-γ and IL-2 and IL-5) on activation. Despite such phenotypic diversity within the individual’s repertoire, all clones had been maintained under identical in vitro culture conditions. Moreover, sequence analyses of TCR β gene usage indicated that in most instances clones from the same donor expressed identical (VDJ)β rearrangements, indicative of a common progenitor cell. FACS analysis of cytoplasmic cytokine production confirmed that for the novel phenotype (IFN-γ and IL-5), both LKs were synthesized at the single cell level. Sibling families of T cell clones, established from a common donor following viral infection but differing in LK secretion, may offer a suitable model system for further studies of signal transduction mechanisms that discriminate between Th1- and Th2-specific responses to a well defined protective Ag.
A Pivotal Role of Cyclin D3 and Cyclin-Dependent Kinase Inhibitor p27 in the Regulation of IL-2-, IL-4-, or IL-10-Mediated Human B Cell Proliferation
Authors: Wagner Eric F. , Hleb Marija , Hanna Nazeeh , Sharma Surendra 
Published: December 2022

AbstractThe functional differences between IgDhighCD38− naive and IgD−CD38− memory (M) or IgDlowCD38+ germinal center (GC) B cells may stem from their variable response to signals that regulate activation, proliferation, and differentiation. In this report, we provide evidence for differential induction of cell cycle regulators in tonsillar human B cell subpopulations that were activated with anti-IgM and anti-CD40 in the presence or absence of IL-2, IL-4, or IL-10. Naive (IgDhigh) B cells exhibited a significant proliferative response to IL-4, but not to IL-2 or IL-10, whereas these cytokines triggered variable levels of growth in the combined GC/M subpopulation (referred to as IgDlow), as measured by [3H]thymidine incorporation. Induction of growth by cytokines in B cell subpopulations strictly correlated with the increased levels of cyclin D3 and cyclin-dependent protein kinase (cdk) 6. Moreover, only cyclin D3/cdk6 complexes were functional as observed in both naive and GC/M B cells stimulated in the presence of IL-4. In addition, active growth was associated with cytokine-mediated elimination of the cell cycle inhibitor p27. The significance of p27 in human B cell cycle was further demonstrated by rapamycin-mediated growth inhibition of IL-4-dependent proliferation, which resulted in strikingly increased p27 levels. Taken together, our findings suggest that cyclin D3, cdk6, and p27 play key roles in IL-2-, IL-4-, and IL-10-mediated human B cell proliferation. Furthermore, these results may provide a molecular basis for different cycling characteristics of naive and GC/M B cell subpopulations.
Surrogate Light Chain Production During B Cell Differentiation: Differential Intracellular Versus Cell Surface Expression
Authors: Wang Yui-Hsi , Nomura Jun , Faye-Petersen Ona Marie , Cooper Max D. 
Published: December 2022

AbstractExpression of the surrogate light (ψL) chain genes encoding the VpreB and λ5/14.1 proteins is restricted to B-lineage cells. Pro-B and pre-B cells produce ψL chains, but whether both employ these as cell surface receptor components remains enigmatic. Recombinant human VpreB protein was used to generate a large panel of monoclonal anti-VpreB Abs to examine this issue. Native ψL chain proteins within pro-B cells as well as those serving as receptor components on pre-B cells were precipitated by 16 of the 26 anti-VpreB Abs. Surrogate light chains were easily detected on pre-B cell lines, whereas these anti-VpreB Abs reacted with pro-B cell lines only after plasma membrane permeabilization. The subpopulation of normal bone marrow cells bearing pre-B receptors included large and small pre-B cells exclusively, although pro-B cells also contained intracellular VpreB. VpreB proteins were not detected on or within B cells in bone marrow or the circulation, but a subpopulation of B cells in germinal centers was found to express the VpreB proteins intracellularly. Surrogate L chains are thus intermittently produced during human B-lineage differentiation, while their role as receptor components appears limited to the pre-B cell stage.
Monocyte-Dependent Death of Freshly Isolated T Lymphocytes: Induction by Phorbolester and Mitogens and Differential Effects of Catalase
Authors: Wesch Daniela , Marx Sibylle , Kabelitz Dieter 
Published: December 2022

AbstractResting T cells are resistant to anti-Fas (CD95) mAb-mediated apoptosis but undergo apoptosis when triggered by anti-CD3 mAb or phorbolester PMA in the presence of PMA-activated monocytes. In this study, PMA, as well as the mitogens PHA and Con A, was found to induce death of resting T cells in the presence of autologous or allogeneic monocytes, while PWM was ineffective. Although several established monocytic and myelocytic cell lines were potent accessory cells for the mitogen-induced expansion of T lymphocytes, they all failed to replace plastic-adherent monocytes in the induction of monocyte-dependent cell death (MDCD) by PMA or PHA. CD45RA-positive cord blood T cells were as susceptible as peripheral blood T cells from adult donors to PMA-stimulated induction of MDCD. Using optimal concentrations of phorbolester, MDCD was inhibited neither by Fas-Fc fusion protein or neutralizing anti-Fas mAb, nor by inhibitors of IL-1β-converting enzyme (ICE)-like proteases. In striking contrast, the H2O2 scavenger catalase completely prevented the PMA-stimulated T cell death, thereby revealing a potent mitogenic activity of PMA for human T cells in the presence of monocytes. Taken together, our results demonstrate that the accessory cell activity of monocytes/macrophages can be separated into “T cell death” and “T cell expansion” costimulatory functions, of which only the latter is mediated by established cell lines. Moreover, our results point to a pivotal role of reactive oxygen intermediates in the execution of MDCD triggered by PMA.
A Subset of CD4+ T Cells Expressing Early Activation Antigen CD69 in Murine Lupus: Possible Abnormal Regulatory Role for Cytokine Imbalance
Authors: Ishikawa Sho , Akakura Shin , Abe Masaaki , Terashima Kazuo , Chijiiwa Karina , Nishimura Hiroyuki , Hirose Sachiko , Shirai Toshikazu 
Published: December 2022

AbstractSystemic lupus erythematosus (SLE), which spontaneously develops in (NZB (New Zealand Black) × NZW (New Zealand White)) F1 mice, is strictly dependent on CD4+ T cells. We found that in these mice with overt SLE, CD4+ T cells expressing CD69 molecules, an early activation Ag, are dramatically increased in peripheral lymphoid tissues and inflammatory infiltrates in the kidney and lung, but not in peripheral blood, while CD8+ and NK1.1+ T cells were virtually CD69−. Various adhesion molecules, including LFA-1, ICAM-1, CD43, CD44, P-selectin, and E-selectin, were up-regulated. Analysis of the TCR repertoire showed no skewed TCR Vβ usage. Studies on in vitro cytokine production of spleen cells on TCR cross-linking indicated that compared with findings in young mice, the aged mice showed severely impaired production of IL-2, IL-3, and IL-4, whereas the levels of IL-10 and IFN-γ remained relatively intact. FACS-sorted CD69−CD4+ T cells from aged mice produced substantial amounts of these cytokines, including IL-2, IL-3, and IL-4, whereas CD69+CD4+ T cells were poor producers. Intriguingly, when cocultured, CD69+CD4+ T cells significantly inhibited the production of IL-2 by CD69−CD4+ T cells. IL-2 production by spleen cells from young mice was also markedly inhibited in the presence of CD69+CD4+ T cells obtained from aged mice. We propose that CD69+CD4+ T cells that are continuously activated by self peptides bound to MHC class II molecules in (NZB × NZW)F1 mice may be involved in the pathogenesis of SLE through abnormal regulatory effects on cytokine balance.
Zinc Bound to the Killer Cell-Inhibitory Receptor Modulates the Negative Signal in Human NK Cells
Authors: Rajagopalan Sumati , Long Eric O. 
Published: December 2022

AbstractThe lysis of target cells by human NK cells is inhibited by several kinds of receptors with varying specificities for the MHC class I molecules of target cells. The requirements for complete inhibition of NK cytotoxicity appear to be complex and not well defined. The HLA-C-specific members of the killer cell-inhibitory receptor (KIR) family, carrying two Ig domains (KIR2D), are unusual among Ig superfamily members in their ability to bind zinc. A role for the zinc-binding site in KIR-mediated inhibition was demonstrated in this study using a functional reconstitution system in NK cells. Replacement of six histidines by alanine residues in putative zinc binding sites of a KIR2D ablated zinc binding and markedly impaired its inhibitory function, but left intact its ability to bind HLA-C and to transduce a positive signal through an immunoreceptor tyrosine-based activation motif grafted onto its cytoplasmic tail. Thus, zinc modulates specifically the negative signal transmitted by this KIR molecule. Mutation of an exposed amino-terminal zinc-binding motif alone was sufficient to impair the inhibitory function of KIR. The data suggest that complete inhibition of HLA-C-specific NK cells requires a zinc-dependent protein-protein interaction via the amino-terminal end of KIR2D.
Pig MHC Mediates Positive Selection of Mouse CD4+ T Cells with a Mouse MHC-Restricted TCR in Pig Thymus Grafts
Authors: Zhao Yong , Swenson Kirsten , Sergio Justin J. , Sykes Megan 
Published: December 2022

AbstractRemarkably normal immune function and specific T cell tolerance to discordant xenogeneic donors can be achieved by grafting fetal pig thymus and liver (FP THY/LIV) tissue to T cell and NK cell-depleted, thymectomized (ATX) mice. To determine whether or not host class II MHC molecules participate in the positive selection of mouse CD4+ T cells in FP THY/LIV grafts, we compared their development in ATX “AND” TCR-transgenic mice with positive selecting or nonselecting host MHC genotypes. Mouse TCR-transgenic CD4 single positive T cells repopulated the periphery significantly and to a similar extent in both T/NK cell-depleted, ATX AND mice with positive-selecting or nonselecting MHC backgrounds after grafting with FP THY/LIV. Therefore, MHC molecules from a widely disparate xenogeneic species can positively select T cells bearing a host class II MHC-restricted TCR without a contribution from the host MHC. These results, in combination with previous studies performed in this model, suggest that the T cell repertoire that is generated by the combination of positive selection on xenogeneic MHC and negative selection on both recipient and xenogeneic porcine MHC is tolerant of both donor and recipient and has sufficient cross-reactivity with host MHC/foreign peptide complexes to confer a high level of immunocompetence. The results have implications for the potential clinical applicability of xenogeneic thymic transplantation and also suggest a predominant role for the TCR recognition of species-conserved MHC residues in positive selection.
Origin and Characteristics of Ultraviolet-B Radiation-Induced Suppressor T Lymphocytes
Authors: Shreedhar Vijay K. , Pride Michael W. , Sun Yan , Kripke Margaret L. , Strickland Faith M. 
Published: December 2022

AbstractCutaneous exposure to low dose (2 kJ/m2) ultraviolet B radiation impairs the induction of contact hypersensitivity (CHS) responses to haptens applied to UV-irradiated skin and induces hapten-specific suppressor T lymphocytes (Ts). Cells collected from the draining lymph nodes of UV-irradiated, FITC-sensitized mice have impaired Ag-presenting activity and induce Ts cells upon injection into syngeneic recipients. This study investigates whether Ts cells originate in the UV-irradiated donor mice or are induced in lymph node cell recipients and the mechanism of suppression. Using congenic mice, we determined that the Ts cells in recipient animals were derived from T cells in the draining lymph nodes of the UV-irradiated donors. Cell lines and clones established from unirradiated and UV-irradiated, FITC-sensitized mice were CD4+, CD8−, TCR-α/β+, MHC restricted, and hapten specific. The T cells proliferated in response to APC sensitized in vivo, but not to APC coupled in vitro with FITC. Cell lines from unirradiated mice were Th1 like, producing large amounts of IFN-γ, but little IL-4 or IL-10, whereas cloned Ts cells from UV-irradiated mice produced IL-10, but no IL-4 or IFN-γ. Ts cells blocked APC functions and IL-12 production in vitro. Injection of 5 × 104 cloned Ts cells into untreated recipients suppressed the induction of CHS. These results suggest that UV radiation can induce a distinct T regulatory type 1-like Ts population that may block the activation of Th1 cell-mediated immune responses.
The Mitogen-Activated Protein Kinase Pathway Inhibits Ceramide-Induced Terminal Differentiation of a Human Monoblastic Leukemia Cell Line, U937
Authors: Ragg Scott J. , Kaga Shuji , Berg Karen A. , Ochi Atsuo 
Published: December 2022

AbstractThis communication describes an extracellular signal-regulated kinase kinase (MEK)-dependent signal transduction pathway that prevents the terminal differentiation of a hemopoietic cell line. Both PMA and the cell-permeable ceramide, C2-ceramide, caused differentiation of U937 cells, but with distinct cell morphology and CD11b/CD14 surface expression. While PMA activated extracellular signal-regulated kinase (ERK), a downstream kinase of Raf-MEK signaling, C2-ceramide activated c-Jun NH2-terminal kinase (JNK), an anchor kinase of stress-induced signaling. Furthermore, only C2-ceramide stimulated an induction of cell cycle arrest that was associated with stable expression of p21CIP1 and retinoblastoma nuclear phosphoprotein dephosphorylation. Expression of p21CIP1 and JNK activation were also observed in sphingosine-treated cells, whereas sphingosine did not induce detectable differentiation. Concomitant stimulation with C2-ceramide and PMA resulted in the PMA phenotype, and cell cycle arrest was absent. ERK activation was enhanced by C2-ceramide plus PMA stimulation, whereas the activation of JNK was aborted. Strikingly, the inhibition of MEK with PD98059 altered the phenotype of C2-ceramide- and PMA-stimulated U937 cells to that of cells treated with C2-ceramide alone. Thus, ERK and JNK pathways deliver distinct signals, and the ERK pathway is dominant to the JNK cascade. Furthermore, differentiation and cell cycle arrest caused by C2-ceramide rely on independent signaling pathways, and JNK is an unlikely signaling element for this differentiation. Importantly, during C2-ceramide and PMA costimulation, the JNK pathway is not simply blocked by ERK activation; rather, cross-talk between these MAP kinase pathways acts to simultaneously augment ERK activity and down-regulate JNK activity.
Covalent Cross-Linking of Immune Complexes by Oxygen Radicals and Nitrite
Authors: Uesugi Masaaki , Hayashi Takeshi , Jasin Hugo E. 
Published: December 2022

AbstractWe have shown that polymorphonuclear neutrophils mediate the covalent cross-linking of immune complexes (ICs) using H2O2 and myeloperoxidase (MPO). Moreover, activated superficial chondrocytes produce large amounts of nitric oxide (NO), suggesting that high concentrations of these radicals may interact at the cartilage surface in rheumatoid arthritis. We describe the effects of the interaction of NO and its decay product, NO2, with H2O2 and MPO on IC cross-linking. Cross-linking was measured by resistance to the guanidine extraction of plastic-bound ICs. The combination of H2O2, MPO, and NO in the absence of O2 did not alter the magnitude of cross-linking. The addition of O2 resulted in a significant enhancement of cross-linking (p &lt; 0.004), suggesting that nitrite was responsible for the increase observed. Indeed, NaNO2 greatly increased H2O2-dependent cross-linking (control: 29.2 ± 3.8; 1 mM NaNO2: 58.4 ± 9.9; 10 mM: 60.4 ± 4.2% cross-linking, p &lt; 0.0002). Sodium azide, which is an inhibitor of MPO, completely inhibited cross-linking. These results indicated that the product of interaction of H2O2 and NO2 mediated by MPO may be responsible for the increase in cross-linking. The generation of nitrotyrosine was demonstrated when NO2 was added to the cross-linking system. Cross-linking was also shown with an O2−-generating system and NO. Peroxynitrite alone mediated cross-linking (100 μM ONOO−: 40.3 ± 1.9% cross-linking; p &lt; 0.002), and the addition of MPO significantly enhanced this effect (100 μM: 57.7 ± 6.0%; p &lt; 0.0002 with respect to no nitrite control). Oxygen radicals and NO are likely to interact at the cartilage surface in inflammatory arthritis, resulting in an increase in oxidative damage within the joint cavity.