Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling.
T cell receptor (TCR) stimulation activates the small GTPase Rap1A, which is reported to antagonize Ras signaling and induces T cell anergy. To address its role in vivo, we generated transgenic mice that constitutively expressed active Rap1A within the T cell lineage. We found that active Rap1A did not interfere with the Ras signaling pathway or antagonize T cell activation. Instead of anergy, the T lymphocytes that constitutively expressed active Rap1A showed enhanced TCR-mediated responses, both in thymocytes and mature T cells. In addition, Rap1A activation was sufficient to induce strong activation of the beta1 and beta2 integrins via an avidity-modulation mechanism. This shows that, far from playing an inhibitory role during T cell activation, Rap1A positively influences T cells by augmenting lymphocyte responses and directing integrin activation.
Sebzda
Eric
E
Lymphocyte Activation Laboratory, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Bracke
Madelon
M
Tugal
Tamara
T
Hogg
Nancy
N
Cantrell
Doreen Ann
DA
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D007108:Immune Tolerance; D019012:Integrin beta1 / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D018821:CD18 Antigens; D019012:Integrin beta1; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins