Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 356K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yamashita, M. Articles by Nakayama, T. Search for Related Content PubMed PubMed Citation Articles by Yamashita, M. Articles by Nakayama, T. Social Bookmarking                            What's this?

Original Article

^a Department of Developmental Immunology, Chiba University School of Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
^b Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
^c Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Company, Limited, Osaka 532, Japan
^d Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo 154, Japan
^e Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912-2600
^f Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6082
Department of Molecular Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.81-43-227-149881-43-226-2200

nakayama{at}med.m.chiba-u.ac.jp

The activation of downstream signaling pathways of both T cell receptor (TCR) and interleukin 4 receptor (IL-4R) is essential for T helper type 2 (Th2) cell development, which is central to understanding immune responses against helminthic parasites and in allergic and autoimmune diseases. However, little is known about how these two distinct signaling pathways cooperate with each other to induce Th2 cells. Here, we show that successful Th2 cell development depends on the effectiveness of TCR-induced activation of calcineurin. An inhibitor of calcineurin activation, FK506, inhibited the in vitro anti-TCR–induced Th2 cell generation in a dose-dependent manner. Furthermore, the development of Th2 cells was significantly impaired in naive T cells from dominant-negative calcineurin A transgenic mice, whereas that of Th1 cells was less affected. Efficient calcineurin activation in naive T cells upregulated Janus kinase (Jak)3 transcription and the amount of protein. The generation of Th2 cells induced in vitro by anti-TCR stimulation was inhibited significantly by the presence of Jak3 antisense oligonucleotides, suggesting that the Jak3 upregulation is an important event for the Th2 cell development. Interestingly, signal transducer and activator of transcription (STAT)5 became physically and functionally associated with the IL-4R in the anti-TCR–activated developing Th2 cells that received efficient calcineurin activation, and also in established cloned Th2 cells. In either cell population, the inhibition of STAT5 activation resulted in a diminished IL-4–induced proliferation. Moreover, our results suggest that IL-4–induced STAT5 activation is required for the expansion process of developing Th2 cells. Thus, Th2 cell development is controlled by TCR-mediated activation of the Ca²⁺/calcineurin pathway, at least in part, by modifying the functional structure of the IL-4R signaling complex.

Key Words: crosstalk • calcineurin transgenic • Janus kinase 3 • signal transducer and activator of transcription 5 • antennapedia peptide

Abbreviations used in this paper: B6, C57BL/6; CN, calcineurin; dn, dominant negative; dnCN Tg, dnCN A transgenic; DO10 Tg, anti-OVA–specific TCR-/β transgenic; HA, hemagglutinin; IRS, insulin receptor substrate; FCM, flow cytometry; Jak, Janus kinase; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T cells; STAT, signal transducer and activator of transcription; Tg, transgenic.

© 2000 The Rockefeller University Press

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS