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 functio...

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Bibliographic Details
Published in:Transplant immunology 2012-06, Vol.26 (4), p.212-219
Main Authors: Haubert, Dirk, Li, Jianping, Saveliev, Alexander, Calzascia, Thomas, Sutter, Esther, Metzler, Barbara, Kaiser, Daniel, Tybulewicz, Victor L.J, Weckbecker, Gisbert
Format: Article
Language:English
Subjects:
Allergy and Immunology
Allograft rejection
Allografts
Animal models
Animals
Cell activation
Cell Proliferation
Cells, Cultured
DNA-Binding Proteins - genetics
GDP
Graft rejection
Graft Rejection - etiology
Graft Rejection - immunology
Graft vs Host Disease - immunology
Heart
Heart Transplantation
Immunosuppression
Immunosuppression Therapy
Isoantigens - immunology
Lymphocyte Activation - genetics
Lymphocytes T
Mice
Mice, Transgenic
Mutation - genetics
Proto-Oncogene Proteins c-vav - genetics
Proto-Oncogene Proteins c-vav - immunology
Proto-Oncogene Proteins c-vav - metabolism
RhoGTPase
T cells
T-cell receptor
T-Lymphocytes - immunology
Transcription Factors - genetics
Vav
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Summary: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.
ISSN:0966-3274
1878-5492
DOI:10.1016/j.trim.2012.03.003