High endothelial venules accelerate naive T cell recruitment by tumor necrosis factor-mediated R-Ras up-regulation.

Abstract Recruitment of naive T cells to lymph nodes is essential for the development of adaptive immunity. Upon pathogen infection, lymph nodes promptly increase the influx of naive T cells from the circulation in order to screen and prime the T cells. The precise contribution of the lymph node vasculature to the regulation of this process remains unclear. Here we show a role for the Ras GTPase, R-Ras, in the functional adaptation of high endothelial venules to increase naive T cell trafficking to the lymph nodes. R-Ras is transiently upregulated in the endothelium of high endothelial venules by inflammatory cytokine TNFα within 24 hours of pathogen inoculation. TNFα induces R-Ras upregulation in endothelial cells via JNK and p38MAPK but not NFκB. Studies of T cell trafficking showed that the loss-of-function of endothelial R-Ras impairs the rapid acceleration of naive T cell recruitment to the lymph nodes upon inflammation. This defect was associated with diminished ability of adoptively transferred naive OT-1 T cells to develop anti-tumor activity against OVA-expressing melanoma. Proteomic analyses suggest that endothelial R-Ras facilitates TNF-dependent transendothelial migration (diapedesis) of naive T cells by modulating molecular assembly at T cell-endothelial cell interface. These findings give new insights into the mechanism of functional adaptation of high endothelial venules to accelerate naive T cell recruitment to the lymph nodes.