LFA-I-mediated regulation of immune response by Rapl.

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Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which LFA-1 and ICAMs are important in this process. However, it is not well understood what signaling molecules regulate this process and how modulation of adhesive events influence 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 TCR triggering and IL-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild type Rap1 enhances these responses, but culminates in apoptosis by Fas/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.