High Endothelial Venules Accelerate Naive T Cell Recruitment by Tumor Necrosis Factor-Mediated R-Ras Upregulation

• Published in: The American journal of pathology Vol. 191; no. 2; pp. 396 - 414
• Main Authors: Sawada, Junko, Perrot, Carole Y., Chen, Linyuan, Fournier-Goss, Ashley E., Oyer, Jeremiah, Copik, Alicja, Komatsu, Masanobu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2021; American Society for Investigative Pathology
• Subjects: Animals; Chemotaxis, Leukocyte - physiology; Endothelial Cells - metabolism; Humans; Lymph Nodes - blood supply; Lymph Nodes - immunology; Lymph Nodes - metabolism; Mice; ras Proteins - metabolism; Regular; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transendothelial and Transepithelial Migration - physiology; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation; Venules - immunology; Venules - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2020.10.009

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 up-regulated in the endothelium of high endothelial venules by the inflammatory cytokine tumor necrosis factor (TNF) within 24 hours of pathogen inoculation. TNF induces R-Ras upregulation in endothelial cells via JNK and p38 mitogen-activated protein kinase but not NF-κB. Studies of T cell trafficking found 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 diminished the ability of naive OT-1 T cells to develop antitumor activity against ovalbumin-expressing melanoma. Proteomic analyses suggest that endothelial R-Ras facilitates TNF-dependent transendothelial migration (diapedesis) of naive T cells by modulating molecular assembly the at T cell–endothelial cell interface. These findings give new mechanistic insights into the functional adaptation of high endothelial venules to accelerate naive T cell recruitment to the lymph nodes.