Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses.
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.
Katagiri
Koko
K
Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Hattori
Masakazu
M
Minato
Nagahiro
N
Kinashi
Tatsuo
T
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000941:Antigens / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion; D002460:Cell Line; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins; D049452:Green Fluorescent Proteins; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008164:Luminescent Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D009113:Muramidase / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D000941:Antigens; D020690:GTPase-Activating Proteins; D007376:Interleukin-2; D008164:Luminescent Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C490403:SIPA1 protein, human; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D010047:Ovalbumin; C421864:hen egg lysozyme; D009113:Muramidase; D020827:rap1 GTP-Binding Proteins