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Vav1 GEF activity is required for T cell mediated allograft rejection

Haubert, Dirk and Calzascia, Thomas and Li, Jianping and Metzler, Barbara and Wieczorek, Grazyna and Kaiser, Daniel and Weckbecker, Gisbert (0012) Vav1 GEF activity is required for T cell mediated allograft rejection. Transplant Immunology. ISSN 0966-3274

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. Disruption of Vav1 GEF activity towards RhoGTPases is thus an attractive approach for immunosuppressive therapy. However, in addition to its GEF activity, Vav1 has been shown to transduce signals independent of its GEF function downstream of the TCR. The contribution of Vav1 GEF-dependent and –independent functions for allogeneic T cell activation is not clear. To address this question, we used knock-in mice containing 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, Vav1 GEF activity strongly contributed to 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 indicate an unexpectedly strong requirement for Vav1 GEF activity for allogeneic T cell activation and graft rejection suggesting that disruption of Vav1 GEF activity alone can induce immunosuppression.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Vav
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4412

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