title: Vav1 GEF activity is required for T cell mediated allograft rejection.
abstract: The GDP exchange factor (GEF) Vav1 is a central signal transducer downstream of the T cell receptor and has been identified as a key factor for T cell activation in the context of allograft rejection. Vav1 has been shown to transduce signals both dependent and independent of its GEF function. The most promising approach to disrupt Vav1 activity by pharmacological inhibition would be to target its GEF function. However, the contribution of Vav1 GEF activity for allogeneic T cell activation has not been clarified yet. To address this question, we used knock-in mice bearing a mutated Vav1 with disrupted GEF activity but intact GEF-independent functions. T cells from these mice showed strongly reduced proliferation and activation in response to allogeneic stimulation. Furthermore, lack of Vav1 GEF activity strongly abrogated the in vivo expansion of T cells in a systemic graft-versus-host model. In a cardiac transplantation model, mice with disrupted Vav1 GEF activity show prolonged allograft survival. These findings demonstrate a strong requirement for Vav1 GEF activity for allogeneic T cell activation and graft rejection suggesting that disruption of Vav1 GEF activity alone is sufficient to induce significant immunosuppression.
authors.affiliation: Novartis Institutes of BioMedical Research, Autoimmunity, Transplantation & Inflammation, 4002 Basel, Switzerland. dirk.haubert@novartis.com
authors.forename: Dirk
authors.initials: D
authors.lastname: Haubert
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.forename: Alexander
authors.initials: A
authors.lastname: Saveliev
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Esther
authors.initials: E
authors.lastname: Sutter
authors.forename: Barbara
authors.initials: B
authors.lastname: Metzler
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaiser
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D016027:Heart Transplantation; D007165:Immunosuppression Therapy; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C528734:GLUT4 enhancer factor, mouse; D007519:Isoantigens; D051567:Proto-Oncogene Proteins c-vav; D014157:Transcription Factors