Journal Article 70–75 kd molecules expressed on LGL and T cells recognized by a mitogenic monoclonal antibody YTA-1; co-modulation and functional association with the interleukin 2 receptor p75 Get access Katsuji Sugie, Katsuji Sugie 1Institute for Immunology, Faculty of Medicine, Kyoto UniversityYoshida, Sakyo, Kyoto 606, Japan22nd Department of Internal Medicine, Faculty of MedicineKyoto University, Shogoin-Kawahara chou, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Yoshiaki Nakamura, Yoshiaki Nakamura 1Institute for Immunology, Faculty of Medicine, Kyoto UniversityYoshida, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Yutka Tagaya, Yutka Tagaya 1Institute for Immunology, Faculty of Medicine, Kyoto UniversityYoshida, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Shigeo Koyasu, Shigeo Koyasu 3Department of Cell Biology, The Tokyo Metropolitan Institute of Medical Science3-18-22, Honokomagome, Bunkyo-ku, Tokyo 113, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Ichiro Yahara, Ichiro Yahara 3Department of Cell Biology, The Tokyo Metropolitan Institute of Medical Science3-18-22, Honokomagome, Bunkyo-ku, Tokyo 113, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Kenji Takakura, Kenji Takakura 1Institute for Immunology, Faculty of Medicine, Kyoto UniversityYoshida, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Shunichi Kumagai, Shunichi Kumagai 22nd Department of Internal Medicine, Faculty of MedicineKyoto University, Shogoin-Kawahara chou, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Hiroo Imura, Hiroo Imura 22nd Department of Internal Medicine, Faculty of MedicineKyoto University, Shogoin-Kawahara chou, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Junji Yodoi Junji Yodoi 1Institute for Immunology, Faculty of Medicine, Kyoto UniversityYoshida, Sakyo, Kyoto 606, Japan Correspodence to: Dr Junji Yodoi, Institute for Immunology, Faculty of Medicine, Kyoto University, Yoshida, Sakyo, Kyoto 606, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar International Immunology, Volume 2, Issue 5, May 1990, Pages 391–397, https://doi.org/10.1093/intimm/2.5.391 Published: 01 May 1990 Article history Received: 09 October 1989 Accepted: 17 February 1990 Published: 01 May 1990
An increase in intracellular cAMP level induced the expression of IL-2R alpha-chain, the 55-kDa component of IL-2R complex, in a human NK-like cell line, YT. We show here that forskolin also induces the expression of IL-2R alpha-chain on mouse large granular lymphocytes (LGL) but not on T cells. In contrast, treatment with a combination of phorbol ester and calcium ionophore, which is a strong inducer of IL-2R alpha-chain on T cells, does not induce the expression of the alpha-chain on LGL cells. Forskolin was shown to activate the transcription of IL-2R alpha-chain gene in YT cells as revealed by the chloramphenicol acetyltransferase assay. Chemical cross-linking experiments using radio-iodinated IL-2 also supported the enhanced expression of IL-2R alpha-chain by treatment with forskolin. In contrast to the alpha-chain, IL-2R beta-chain was not induced by forskolin as revealed by flow cytofluorometry with a mAb against the beta-chain molecule. These results indicate that the activation of adenylate cyclase induces or/and enhance the expression of IL-2R alpha-chain at the transcriptional level in LGL/NK cells including mouse LGL and human YT cell, which leads to the enhanced expression of high affinity IL-2 receptors.
T cell receptor (TCR) antagonists inhibit antigen-induced T cell activation and by themselves fail to induce phenotypic changes associated with T cell activation. However, we have recently shown that TCR antagonists are inducers of antigen-presenting cell (APC)–T cell conjugates. The signaling pathway associated with this cytoskeleton-dependent event appears to involve tyrosine phosphorylation and activation of Vav. In this study, we investigated the role played by the protein tyrosine kinases Fyn, Lck, and ZAP-70 in antagonist-induced signaling pathway. Antagonist stimulation increased tyrosine phosphorylation and kinase activity of Fyn severalfold, whereas little or no increase in Lck and ZAP-70 activity was observed. Second, TCR stimulation of Lck − , Fyn hi Jurkat cells induced strong tyrosine phosphorylation of Vav. In contrast, minimal increase in tyrosine phosphorylation of Vav was observed in Lck hi , Fyn lo Jurkat cells. Finally, study of T cells from a Fyn-deficient TCR transgenic mouse also showed that Fyn was required for tyrosine phosphorylation and activation of Vav induced by both antagonist and agonist peptides. The deficiency in Vav phosphorylation in Fyn-deficient T cells was associated with a defect in the formation of APC–T cell conjugates when T cells were stimulated with either agonist or antagonist peptide. We conclude from these results that Vav is a selective substrate for Fyn, especially under conditions of low-affinity TCR-mediated signaling, and that this signaling pathway involving Fyn, Vav, and Rac-1 is required for the cytoskeletal reorganization that leads to T cell–APC conjugates and the formation of the immunologic synapse.
T cell receptor antagonists inhibit T cell activation by antigen, and by themselves fail to induce phenotypic changes associated with T cell activation. However, they can induce limited tyrosine phosphorylation of TCRζ chain. Here we show that TCR antagonists are potent inducers of APC-T cell conjugates, cytoskeletal reorganization, and capping of certain T cell proteins. These events are associated with a signaling pathway involving tyrosine phosphorylation of Vav and SLP-76, activation and capping of Rac-1, a protein previously linked with cytoskeletal reorganization, and activation of JNK. The finding that antagonist peptides stimulate this pathway, while failing to stimulate other TCR-mediated signaling pathways, indicates the presence in T cells of a hierarchy of signaling that is sensitive to the avidity of Ag / MHC-TCR interaction.
T helper 2 (Th2) cells are critical to the induction of IgE antibody and allergic inflammation, but how the pathological pathways are controlled in nonallergic individuals remains unclear. Here we report that glycosylation-inhibiting factor (GIF) suppresses Th2 effector generation. GIF is a cytokine encoded by the same gene that codes for macrophage migration inhibitory factor (MIF). GIF-deficient mice demonstrated enhanced T-dependent antibody formation especially of IgE isotype and allergic airway inflammation with the generation of regulatory T cells unaffected. GIF-deficient macrophages and dendritic cells revealed normal responsiveness to toll-like receptor (TLR) ligands. GIF undergoes a unique posttranslational modification, cysteinylation. The modified GIF, mainly secreted by activated T cells derived from CD4(+)CD25(-) cells, inhibited IL-4 production by the same cells whereas the unmodified GIF showed no effect. Bone marrow chimera experiment demonstrated that T cell-derived GIF suppressed the generation of Th effectors that secrete IL-4. During the first 24 h of CD3/CD28 stimulation in vitro, GIF secreted from naïve CD4 cells acted on the same cells, maintained nuclear factor of activated T cells (NFAT)c2 in the nucleus, and repressed IL-4 mRNA levels. Thus, GIF represents a self-regulatory mechanism of Th2 cell generation from naïve CD4 cells, in which the posttranslational modification plays a crucial role.
T cell helper type 2 (Th2) differentiation is driven by a source of IL-4 receptor (IL-4R) that mobilizes IL-4R signaling pathways and the transcription factor GATA-3. Naïve CD4 cells can secrete IL-4 independently of IL-4R signals, but how this secretion is regulated is not understood. Here we demonstrate that costimulation through the tumor necrosis factor receptor family molecule OX40, in synergy with CD28, is essential for high levels of nuclear factor of activated T cells c1 to accumulate in the nucleus of a recently activated naïve T cell. This action is not dependent on either IL-4R or IL-2R signals and results in OX40 controlling initial naïve T cell IL-4 transcription. OX40 signals subsequently enhance nuclear GATA-3 accumulation through an IL-4R-dependent action, leading to Th2 differentiation. These data show that, in the absence of an exogenous source of IL-4, OX40 provides a critical synergistic and temporal signal with other noncytokine receptors to modulate nuclear factor of activated T cells c1 and to promote optimal Th2 generation.
The present study unequivocally demonstrated the expression of CD28 on murine bone marrow-derived cultured mast cells and a mast cell line, MCP-5. Stimulation of surface CD28 molecules on mast cells with anti-CD28 mAbs induced tyrosine phosphorylation of cellular proteins, including several protein tyrosine kinases and their substrates, such as Itk/Emt (Emt), Btk, Syk, c-Cbl, Shc, and Vav. CD28-stimulated tyrosine phosphorylation was followed by a rebound hypophosphorylation. Interestingly, CD28 stimulation alone elicited a low level secretion of TNF-alpha. On the other hand, cross-linking of the high affinity IgE receptor (Fc epsilon RI) on mast cells induces a set of activation events, i.e., degranulation, secretion of eicosanoids, secretion of cytokines, and DNA synthesis. Concurrent stimulation of mast cells through CD28 enhanced Fc epsilon RI-induced TNF-alpha secretion in a dose-dependent manner. Together, the present data suggest a role for CD28-mediated costimulation of mast cells in the initiation and progression of allergic responses and other diseases.
