Vav1 GEF activity is required for T cell mediated allograft rejection
| Autor: | Barbara Metzler, Jianping Li, Thomas Calzascia, Daniel Kaiser, Dirk Haubert, Gisbert Weckbecker, Esther Sutter, Victor L. J. Tybulewicz, Alexander Saveliev |
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| Rok vydání: | 2012 |
| Předmět: |
Graft Rejection
Isoantigens VAV1 animal structures T cell T-Lymphocytes Immunology Vav T cells Graft vs Host Disease Context (language use) Stimulation Mice Transgenic Biology Lymphocyte Activation environment and public health Article Allograft rejection Mice medicine Immunology and Allergy Animals RhoGTPase Proto-Oncogene Proteins c-vav Transcription factor Cells Cultured Cell Proliferation Immunosuppression Therapy Transplantation Cell growth T-cell receptor fungi Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) medicine.anatomical_structure Mutation Heart Transplantation biological phenomena cell phenomena and immunity Transcription Factors |
| Zdroj: | Transplant Immunology |
| ISSN: | 1878-5492 |
| Popis: | 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. Highlights ► The contribution of Vav1 GEF activity to allograft rejection was addressed. ► T cells with disrupted GEF activity showed reduced proliferation and activation. ► Mice with disrupted Vav1 GEF activity showed prolonged cardiac allograft survival. ► Vav1 GEF activity significantly contributes to T cell-mediated allograft rejection. |
| Databáze: | OpenAIRE |
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