T Cell Receptorâ Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex

Hdl Handle:
http://hdl.handle.net/10675.2/559
Title:
T Cell Receptorâ Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex
Authors:
Yamashita, Masakatsu; Katsumata, Makoto; Iwashima, Makio; Kimura, Motoko; Shimizu, Chiori; Kamata, Tohru; Shin, Tahiro; Seki, Nobuo; Suzuki, Seiichi; Taniguchi, Masaru; Nakayama, Toshinori
Abstract:
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-TCRâ 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 Aα 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-TCRâ 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-4â induced proliferation. Moreover, our results suggest that IL-4â 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.
Citation:
J Exp Med. 2000 Jun 5; 191(11):1869-1880
Issue Date:
5-Jun-2000
URI:
http://hdl.handle.net/10675.2/559
PubMed ID:
10839803
PubMed Central ID:
PMC2213529
Type:
Article
ISSN:
1540-9538
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorYamashita, Masakatsuen_US
dc.contributor.authorKatsumata, Makotoen_US
dc.contributor.authorIwashima, Makioen_US
dc.contributor.authorKimura, Motokoen_US
dc.contributor.authorShimizu, Chiorien_US
dc.contributor.authorKamata, Tohruen_US
dc.contributor.authorShin, Tahiroen_US
dc.contributor.authorSeki, Nobuoen_US
dc.contributor.authorSuzuki, Seiichien_US
dc.contributor.authorTaniguchi, Masaruen_US
dc.contributor.authorNakayama, Toshinorien_US
dc.date.accessioned2012-10-26T16:26:40Z-
dc.date.available2012-10-26T16:26:40Z-
dc.date.issued2000-06-5en_US
dc.identifier.citationJ Exp Med. 2000 Jun 5; 191(11):1869-1880en_US
dc.identifier.issn1540-9538en_US
dc.identifier.pmid10839803en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/559-
dc.description.abstractThe 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-TCRâ 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 Aα 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-TCRâ 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-4â induced proliferation. Moreover, our results suggest that IL-4â 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.en_US
dc.rights© 2000 The Rockefeller University Pressen_US
dc.subjectOriginal Articleen_US
dc.titleT Cell Receptorâ Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complexen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2213529en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics-

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