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

Abstract

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 p27^Kip1. Our study indicates that the activation state of Rap1 has a decisive effect on the T-cell response to antigen.

We thank P. M. Allen for the 3A9 T-cell hybridoma line, D. Gerlier for CH27 B-lymphoblastoid cells, T. Kakiuchi for A20.2J B-cell lymphoma cells, Y. Ohta for OVA-specific I-A^d-restricted T-cell lines, and S.-K. Jung for chimeric Fas-Fc or TNFR1-Fc fusion proteins. We are grateful to T. Katagiri for helpful discussions.

This work was supported in part by a grant-in aid from the Ministry of Education, Science, Sports, and Culture of Japan and the Wehara Memorial Foundation.