HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 39, 28666-28678, September 29, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/39/28666    most recent M604081200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tan, A. H.-M. Articles by Lam, K.-P. Search for Related Content PubMed PubMed Citation Articles by Tan, A. H.-M. Articles by Lam, K.-P. Social Bookmarking                      What's this?

Regulation of Mouse Inducible Costimulator (ICOS) Expression by Fyn-NFATc2 and ERK Signaling in T Cells^*

From the Laboratory of Immune Regulation, Singapore Institute of Immunology, Proteos, Singapore 138673, Singapore

The inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is rapidly induced upon T cell activation. Although the critical role of ICOS in costimulating T cell responses is well documented, little is known of the intracellular signaling pathways and mechanisms that regulate ICOS expression. Here, we report that Fyn, NFAT, and ERK signaling influence ICOS expression as various chemical inhibitors, such as PP2 that targets Src kinases, U0126 that targets MEK1/2, and cyclosporin A or FK506 that targets calcineurin and thereby affects NFAT, attenuate T cell receptor-mediated ICOS induction. Moreover, ectopic expression of NFATc2 or a constitutively active MEK2 amplifies ICOS transcription and transactivates a 288-bp core region of the icos promoter in luciferase reporter assays. We also identify a site on the icos promoter that is sensitive to ERK signaling and further show that NFATc2 can bind the icos promoter in vivo and that this binding is diminished when Fyn signaling is ablated. The normal activation of ERK but reduced nuclear translocation of NFATc2 in Fyn^–/– CD4⁺ T cells further suggest that Fyn and NFATc2 act in a common axis, separate from that involving ERK, to drive ICOS transcription. Taken together, our findings indicate that Fyn-calcineurin-NFATc2 and MEK2-ERK1/2 are two independent signaling pathways that cooperate to control T cell receptor-mediated ICOS induction.

Received for publication, April 28, 2006 , and in revised form, July 31, 2006.

^* This work was supported by grants from the Biomedical Research Council of the Agency for Science, Technology and Research, Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Laboratory of Immune Regulation, Singapore Institute of Immunology, 61 Biopolis Dr., Proteos, Singapore 138673, Singapore. Tel.: 65-65869649; Fax: 65-67791117; E-mail: mcblamkp{at}imcb.a-star.edu.sg.

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

This article has been cited by other articles:

				H. Lu, B. L. F. Kaplan, T. Ngaotepprutaram, and N. E. Kaminski Suppression of T cell costimulator ICOS by {Delta}9-tetrahydrocannabinol J. Leukoc. Biol., February 1, 2009; 85(2): 322 - 329. [Abstract] [Full Text] [PDF]

				M. Watanabe, Y. Takagi, M. Kotani, Y. Hara, A. Inamine, K. Hayashi, S. Ogawa, K. Takeda, K. Tanabe, and R. Abe Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses J. Immunol., April 15, 2008; 180(8): 5222 - 5234. [Abstract] [Full Text] [PDF]

				A. H.-M. Tan, S. Y.-P. Goh, S.-C. Wong, and K.-P. Lam T Helper Cell-specific Regulation of Inducible Costimulator Expression via Distinct Mechanisms Mediated by T-bet and GATA-3 J. Biol. Chem., January 4, 2008; 283(1): 128 - 136. [Abstract] [Full Text] [PDF]