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Molecular and Cellular Biology, February 2002, p. 1001-1015, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1001-1015.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rap1 Functions as a Key Regulator of T-Cell and Antigen-Presenting Cell Interactions and Modulates T-Cell Responses

Koko Katagiri,1 Masakazu Hattori,2 Nagahiro Minato,2 and Tatsuo Kinashi1*

Department of Molecular Immunology and Allergy, Graduate School of Medicine,1 Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto 606-8501, Japan2

Received 19 July 2001/ Returned for modification 7 October 2001/ Accepted 13 November 2001

Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecules (ICAMs) are important. However, it is not well understood what signaling molecules regulate this process and how the modulation of adhesive events influences T-cell activation. Here we show that Rap1 is activated in T cells in an antigen-dependent manner and accumulated at the contact site of T-cell and antigen-loaded APC. Inhibition of Rap1 activation by a dominant-negative Rap1 or SPA-1, a Rap1 GTPase-activating protein, abrogates LFA-1-ICAM-1-mediated adhesive interactions with antigen-pulsed APC and the subsequent T-cell-receptor triggering and interleukin-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild-type Rap1 enhances these responses but culminates in apoptosis by Fas and FasL. Thus, Rap1 functions as a key regulator of T-cell and APC interactions and modulates T-cell responses from productive activation to activation-induced cell death by regulating the strength of adhesive interactions. Moreover, constitutive Rap1 activation rendered T cells unresponsive with accumulation of p27Kip1. Our study indicates that the activation state of Rap1 has a decisive effect on the T-cell response to antigen.

* Corresponding author. Mailing address: Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-771-8159. Fax: 81-75-771-8184. E-mail: tkinashi{at}mfour.med.kyoto-u.ac.jp.

Molecular and Cellular Biology, February 2002, p. 1001-1015, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1001-1015.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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