bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two Types of Anti-TL (Thymus Leukemia) CTL Clones with Distinct Target Specificities: Differences in Cytotoxic Mechanisms and Accessory Molecule Requirements
Authors: Tsujimura Kunio , Takahashi Toshitada , Iwase Shigeru , Matsudaira Yasue , Kaneko Yoko , Yagita Hideo , Obata Yuichi 
Published: January 2023

Abstract
TCRαβ CTL clones recognizing mouse thymus leukemia (TL) Ags were established and categorized into two groups: those killing any TL+ target cells (type I) and those killing only TL+ Con A blasts (type II). Cold target inhibition assays showed that the antigenic determinant(s) recognized by type II clones are expressed not only on TL+ Con A blasts but also on other TL+ target cells. The relation of the target specificity to the killing machinery and the accessory molecules involved in cytotoxicity were therefore analyzed using four representative clones selected from each type. Of the target cells tested, Fas was only expressed on Con A blasts, indicating that Fas ligand (FasL)-dependent cytotoxicity is limited to such cells. All four type II and one of four type I clones expressed FasL on the surface, while both types contained perforin in the cytoplasm. Blocking studies using neutralizing anti-FasL mAbs and concanamycin A (CMA), a selective inhibitor of the perforin pathway, suggested that type I clones kill target cells by way of perforin, while type II clones kill TL+ Con A blasts through FasL together with perforin. For their cytotoxicity, type I CTLs require a signal through CD8, while type II require LFA-1/ICAM-1 interactions. Type II clones also need a costimulatory signal through an unknown molecule for perforin-dependent cytotoxicity. These results taken together suggest that the difference in the target specificity of anti-TL CTL clones is due to variation in the killing machineries and the dependence on accessory molecules.
A Pathogenic Role of IL-12 in Blood-Stage Murine Malaria Lethal Strain Plasmodium berghei NK65 Infection
Authors: Yoshimoto Takayuki , Takahama Yasuhiro , Wang Chrong-Reen , Yoneto Toshihiko , Waki Seiji , Nariuchi Hideo 
Published: January 2023

Abstract
We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-γ, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-α, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-γ. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-γ in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-γ production rather than the protection.
Cutting Edge: JAK3 Activation and Rescue of T Cells from HIV gp120-Induced Unresponsiveness
Authors: Selliah Nithianandan , Finkel Terri H. 
Published: January 2023

AbstractIn early HIV disease, immunodeficiency is characterized by the inability of CD4+ T cells to produce a critical cytokine, IL-2, and to express the receptor for IL-2 (IL-2R) in response to antigenic or mitogenic stimulation. The shared common γ-chain (γc) of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function. Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3. Stimulation through the γc-related cytokine receptors restores JAK3 expression and activation and rescues CD4-mediated T cell unresponsiveness. Collectively, these data argue that inhibition of JAK3 expression and activation may, in part, explain the T cell dysfunction seen in early HIV disease. In addition, rescue from gp120-mediated T cell unresponsiveness by activation of JAK3 suggests a novel therapeutic approach for enhancing immune function in HIV disease.
Specific Immune Induction Following DNA-Based Immunization Through In Vivo Transfection and Activation of Macrophages/Antigen-Presenting Cells
Authors: Chattergoon Michael A. , Robinson Tara M. , Boyer Jean D. , Weiner David B. 
Published: January 2023

Abstract
The initiation of an adaptive immune response requires Ag presentation in combination with the appropriate activation signals. Classically, Ag presentation and immune activation occur in the lymph node and spleen, where a favorable organ architecture and rich cellular help can enhance the process. Recently, several investigators have reported the use of DNA expression cassettes to elicit cellular and humoral immunity against diverse pathogens. Although the immune mechanisms involved are still poorly understood, plasmid inoculation represents a model system for studying immune function in response to invading pathogens. In this report, we demonstrate the presence of activated macrophages or dendritic cells in the blood lymphocyte pool and peripheral tissues of animals inoculated with DNA expression cassettes. These cells are directly transfected in vivo, present Ag, and display the surface proteins CD80 and CD86. Our studies indicate that these cells function as APC and can activate naive T lymphocytes. They may represent an important first step APC in genetic immunization and natural infection.
Differential Involvement of a Fas-CPP32-Like Protease Pathway in Apoptosis of TCR/CD9-Costimulated, Naive T Cells and TCR-Restimulated, Activated T Cells
Authors: Park Cheung-Seog , Yashiro Yumi , Tai Xu-Guang , Toyo-oka Kazuhito , Hamaoka Toshiyuki , Yagita Hideo , Okumura Ko , Neben Steven , Fujiwara Hiromi 
Published: January 2023

Abstract
Our previous study showed that CD9 costimulation of TCR-triggered naive T cells elicits activation ([3H]TdR incorporation) that is similar to CD28 costimulation; however, unlike CD28 costimulation, CD9 costimulation results in apoptosis of these previously activated T cells. Here, we investigated whether the apoptosis occurring after TCR/CD9 stimulation is associated with a death pathway involving Fas stimulation and Fas-mediated caspase activation as observed in activation-induced cell death (AICD). In contrast to AICD, the apoptosis resulting from TCR/CD9 stimulation in C57BL/6 T cells was independent of Fas, because this form of apoptosis was not prevented by anti-Fas ligand mAb and was also induced in MRL/lpr T cells. AICD was observed at 12 h after the restimulation of activated T cells with anti-CD3 and reached a peak level at 24 h after this restimulation. CPP32-like protease activity was detected during AICD. Although TCR/CD9 stimulation-associated apoptosis was observed at 24 h after the stimulation of naive T cells and reached a peak level at 36 h after this stimulation, CPP32-like protease activity in these T cells was only marginal at all time points. Nevertheless, both forms of apoptosis were prevented similarly by two different peptide-based caspase inhibitors. These results indicate that the apoptosis that follows the T cell activation which is induced as a result of CD9 costimulation does not involve a Fas-CPP32-like protease pathway, but suggest that different caspase members are likely to be critical in this form of apoptosis.
Intracellular Formation and Cell Surface Expression of a Complex of an Intact Lysosomal Protein and MHC Class II Molecules
Authors: Arunachalam Balasubramanian , Pan Mary , Cresswell Peter 
Published: January 2023

AbstractThe generation of invariant chain-free MHC class II molecules and their association with endocytically generated peptides are thought to occur in specialized lysosome-like compartments called MIICs (MHC class II compartments). A number of in vitro studies have shown that large denatured proteins can bind to class II molecules, and that class II association can protect the bound segment of protein from proteolytic degradation. In this work, we present what we believe is the first example of an intact endogenous protein (IP30) binding in an allele-dependent fashion to class II molecules in vivo. IP30 is an IFN-γ-inducible 35-kDa glycoprotein that localizes in MIICs. In this study, we show that intact IP30 binds to certain HLA-DR alleles via an N-terminal prosequence. The association takes place in the endocytic pathway following removal of invariant chain from class II molecules and before their cell surface expression. We also show that DR-IP30 complexes are SDS stable. The potential precursor-product relationship between DR-IP30 complexes and the DR-peptide complex is discussed.
T Cell Renewal Rates, Telomerase, and Telomere Length Shortening
Authors: De Boer Rob J. , Noest André J. 
Published: January 2023

Abstract
Measurements on the average telomere lengths of normal human naive and memory T cells suggested that 1) naive and memory human T cells have similar division rates, and 2) that the difference between naive and memory cells reflects the degree of clonal expansion during normal immune reactions. Here we develop mathematic models describing how the population average of telomere length depends on the cell division rates of naive and memory T cells during clonal expansion and normal renewal. The results show that 1) telomeres shorten with twice the cell division rate, 2) that the conventional approach of estimating telomere length shortening per mean population doubling gives rise to estimates that are 39% larger than the “true” loss per cell division, 3) that naive and memory T cells are expected to shorten their telomeres at rates set by the division rate of the naive T cells only, i.e., irrespective of the division rate of memory T cells, 4) that the measured difference in the average telomere length between naive and memory T cells may largely reflect the difference in renewal rates between these subpopulations rather than the clonal expansion, and 5) that full telomerase compensation during clonal expansion is consistent with all data on the shortening of telomere length in, and between, naive and memory T cells. Thus we reconcile the apparent contradictions between the demonstrated difference in division rates between human naive and memory T cells and their similar rates of telomere shortening, and the demonstrated telomere shortening in the presence of telomerase activity.
Dipeptidyl Peptidase I and Granzyme A Are Coordinately Expressed During CD8+ T Cell Development and Differentiation
Authors: Mabee Christopher L. , McGuire Michael J. , Thiele Dwain L. 
Published: January 2023

AbstractDipeptidyl peptidase I (DPPI) is a granule protease that plays a requisite role in processing the proenzyme form of the CTL granule serine proteases (granzymes). This study assesses DPPI mRNA and enzyme expression during T lymphocyte ontogeny and CTL differentiation. The most immature CD3−CD4−CD8− thymocytes were found to express &gt;40-fold higher levels of DPPI mRNA, although levels of DPPI enzymatic activity in CD3−CD4−CD8− thymocytes were only modestly higher than those seen for CD4+CD8+ or CD4+CD8− thymocytes. More mature CD8+CD4− thymocytes and CD8+ splenocytes expressed significantly higher levels of DPPI mRNA and enzymatic activity than CD4+CD8+ or CD4+CD8− thymocytes. Granzyme A mRNA expression was observed in DPPI expressing CD3−CD4−CD8− and CD8+CD4− thymocytes and was also observed in CD8+CD4− splenocytes; however, expression was not observed in CD4+CD8+ or CD4+CD8− thymocytes. Both DPPI mRNA and granzyme A mRNA expression in CD8+ T cells decreased to very low or undetectable levels during the first 48 h after allostimulation in MLCs. However, peak levels of both DPPI and granzyme A expression were observed later in the course of CD8+ T cell responses to alloantigen, with DPPI mRNA expression peaking on either day 3 or day 4 and granzyme A expression peaking at the end of a 5-day MLR. These data indicate that DPPI is expressed at all stages of T cell ontogeny and differentiation in which granzyme A mRNA is detected; consequently, DPPI appears to be available for the processing and activation of granzyme A during both CD8+ T cell development and differentiation.
Molecular Mechanisms of the Induction of IL-12 and Its Inhibition by IL-10
Authors: Aste-Amezaga Miguel , Ma Xiaojing , Sartori Alexandrina , Trinchieri Giorgio 
Published: January 2023

AbstractExogenously added IL-10 rapidly inhibited Staphylococcus aureus- or LPS-induced cytokine mRNA expression in human PBMCs and monocytes, with a maximal effect observed when IL-10 was added from 20 h before until 1 h after the addition of the inducers. Nuclear run-on assays revealed that the inhibition of IL-12 p40, IL-12 p35, and TNF-α was at the gene transcriptional level and that the addition of IL-10 to S. aureus- or LPS-treated PBMCs did not affect mRNA stability. The inhibitory activity of IL-10 was abrogated by cycloheximide (CHX), suggesting the involvement of a newly synthesized protein(s). The addition of CHX at 2 h before S. aureus or LPS also inhibited the accumulation of IL-12 p40 mRNA, but did not inhibit IL-12 p35 and TNF-α mRNA. This finding suggests that p40 transcription is regulated through a de novo synthesized protein factor(s), whereas the addition of CHX at 2 h after S. aureus activation caused superinduction of the IL-12 p40, IL-12 p35, and TNF-α genes. These results indicate that in human monocytes, the mechanism(s) of IL-10 suppression of both IL-12 p40 and IL-12 p35 genes is primarily seen at the transcriptional level, and that the induction of the IL-12 p40 and p35 genes have different requirements for de novo protein synthesis.
Conservation of Structure and Function Between Human and Murine IL-16
Authors: Keane Joseph , Nicoll John , Kim Sue , Wu David M. H. , Cruikshank William W. , Brazer William , Natke Barbara , Zhang Yujun , Center David M. , Kornfeld Hardy 
Published: January 2023

AbstractIL-16 is a proinflammatory cytokine that signals via CD4, inducing chemotactic and immunomodulatory responses of CD4+ lymphocytes, monocytes, and eosinophils. Comparative analysis of murine and human IL-16 homologs could reveal conserved structures that would help to identify key functional regions of these cytokines. To that end, we cloned the murine IL-16 cDNA and found a high degree of amino acid similarity comparing the predicted murine and human IL-16 precursor proteins (pro-IL-16). The highest similarity (82.1%) was found in the C-terminal region, which is cleaved from pro-IL-16 to yield biologically active IL-16. Chemotaxis experiments with IL-16 of murine and human origin, using murine splenocytes or human T lymphocytes as targets, showed cross-species stimulation of motility. Synthetic oligopeptides and anti-peptide Ab were produced, based on the sequences of three predicted hydrophilic domains of IL-16 potentially presented in exposed positions. None of these peptides had intrinsic IL-16 bioactivity, but one (corresponding to a hydrophilic C-terminal domain of IL-16) partially displaced binding of OKT4 mAb to human lymphocytes. This peptide, and its cognate Ab, also inhibited IL-16 chemoattractant activity for human and murine cells. These studies demonstrate a high degree of structural and functional similarity between human and murine IL-16 and suggest that amino acids in the C terminus are critical for its chemoattractant function. The data suggest cross-species conservation of IL-16 receptor structures as well. Inhibitory peptides may be useful in disease states where the proinflammatory functions of IL-16 are detrimental to the host.
Influenza A Virus-Induced IFN-α/β and IL-18 Synergistically Enhance IFN-γ Gene Expression in Human T Cells
Authors: Sareneva Timo , Matikainen Sampsa , Kurimoto Masashi , Julkunen Ilkka 
Published: January 2023

Abstract
T cells contribute significantly the to host’s early defense against viral and bacterial infections and are essential for clearance of the pathogen. IFN-γ, a product of activated T and NK cells, has, in addition to its direct antimicrobial activity, a major role in activating cell-mediated immunity. Here we report that cytokines secreted by influenza A virus-infected macrophages are able to induce IFN-γ synthesis in human T cells. Influenza A virus-infected human peripheral macrophages secreted IFN-α/β, TNF-α, IL-1β, and a recently identified cytokine, IL-18 (or IFN-γ-inducing factor), whereas the production of IL-12 was not detected. Supernatants collected from virus-infected macrophages induced rapid IFN-γ mRNA expression and protein production in T cells. This was down-regulated by the addition of neutralizing anti-IFN-α/β Abs, whereas neutralizing anti-IL-12 Abs had no effect on IFN-γ gene expression. Exogenously added IFN-α/β also rapidly stimulated the synthesis of IFN-γ mRNA in T cells independently of protein synthesis. IL-18 synergized with IFN-α to up-regulate IFN-γ gene expression and protein production. The data suggest that IFN-α/β and IL-18 produced by macrophages during virus infection may act together to induce IFN-γ synthesis and, consequently, may play an important role for both of these cytokines in the development of Th1-type immune responses.
Cutting Edge Commentary: Differential TCR Signaling and the Generation of Memory T Cells
Authors: Farber Donna L. 
Published: January 2023

AbstractThere are currently two models for the generation of memory T cells: 1) memory T cells arise directly from activated effector T cells that have reverted to the resting state via an unknown mechanism; and 2) memory T cells are generated directly from naive T cells, bypassing an effector stage. I discuss here how recent results on the activation and signaling requirements of naive vs memory CD4 T cells favor the second model and how differential signaling of naive T cells may direct their developmental outcome.
Intercellular Adhesion Molecule-1 and Leukocyte Function-Associated Antigen-3 Provide Costimulation for Superantigen-Induced T Lymphocyte Proliferation in the Absence of a Specific Presenting Molecule
Authors: Lamphear James G. , Stevens Kristin Reda , Rich Robert R. 
Published: January 2023

Abstract
Bacterial superantigens can bind TCR in the absence of MHC class II molecules and activate T lymphocytes when cocultured with certain class II-deficient accessory cells. It has not been determined, however, whether these accessory cells provide direct costimulation to the T cell or serve to present superantigens via a nonconventional ligand. We have identified a human adenocarcinoma cell line, SW480, that assists in the activation of human T cells by the staphylococcal enterotoxins B (SEB), C1 (SEC1), and D (SED), but not SEA, SEC2, SEC3, or SEE. SW480 cells did not express class II molecules, and anti-class II mAbs did not inhibit T cell proliferation, supporting the hypothesis that class II is not absolutely required for enterotoxin-mediated T cell activation. The TCR Vβ profile of T cells stimulated by SEB plus SW480 cells was similar to that of T cells stimulated by SEB plus class II+ APC, indicating that TCR-SEB interactions were preserved in the absence of class II molecules. Binding studies failed to detect specific association of SEB with SW480 cells, suggesting that SW480 cells do not express receptors for enterotoxin. SEB coupled to beads, however, stimulated T cell proliferation, but only in the presence of SW480 cells. SW480 cells express both ICAM-1 and LFA-3 molecules, and the addition of Abs to these receptors inhibited T cell proliferation. These findings support a model in which certain enterotoxins engage the TCR independent of MHC class II or other specific presenting molecules and induce T cell proliferation with signals provided by nonconventional accessory cells.
Induction of Tyrosine Phosphorylation in Human MHC Class II-Positive Antigen-Presenting Cells by Stimulation with Contact Sensitizers
Authors: Kühn Ulrich , Brand Pia , Willemsen Judith , Jonuleit Helmut , Enk Alexander H. , van Brandwijk-Petershans Renate , Saloga Joachim , Knop Jürgen , Becker Detlef 
Published: January 2023

AbstractTo investigate the intracellular signaling mechanisms involved in the activation of APC by contact sensitizers, we studied the induction of tyrosine phosphorylation by these agents. Selective analysis of phosphotyrosine (p-tyr) in human Langerhans cells and different mononuclear cell types was achieved using a multicolor flow-cytometric technique. Stimulation with contact sensitizers revealed a distinct increase in p-tyr exclusively for MHC class II-positive cells. For different haptens, irritants, as well as activators of distinct signal transduction pathways, it was demonstrated that only strong sensitizers or the protein tyrosine phosphatase inhibitor sodium orthovanadate or cross-linking of MHC class II molecules were able to induce formation of p-tyr in human blood-derived dendritic cells serving as model for the dendritic cell family. This event required physiologic cell culture conditions and was blocked by specific inhibitors of protein tyrosine kinases. No evidence for the inhibition of protein tyrosine phosphatases by haptens was found. Western blot analysis of monocyte-enriched populations revealed an augmented phosphorylation of distinct proteins after hapten stimulation partly resembling the pattern noticed after cross-linking of HLA-DR molecules. In dendritic cells generated from mononuclear progenitors, the protein tyrosine kinase inhibitor genistein was able to block tyrosine phosphorylation as well as production of IL-1β mRNA transcripts. Our data underline the unique capacity of haptens to activate APC and the important role of tyrosine phosphorylation for this process.