CD4(+) T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema

• Type of Material: Article
• Authors: Gabriela Garcia Nores, Emory University; Catherine L. Ly, Memorial Sloan Kettering Cancer Center; Daniel Cuzzone, Emory University; Raghu P. Kataru, Memorial Sloan Kettering Cancer Center; Geoffrey E. Hespe, Memorial Sloan Kettering Cancer Center; Jeremy S. Torrisi, Memorial Sloan Kettering Cancer Center; Jung Ju Huang, Memorial Sloan Kettering Cancer Center; Jason C. Gardenier, Memorial Sloan Kettering Cancer Center; Ira L. Savetsky, Memorial Sloan Kettering Cancer Center; Matthew D. Nitti, Memorial Sloan Kettering Cancer Center; Jessie Z. Yu, Memorial Sloan Kettering Cancer Center; Sonia Rehal, Memorial Sloan Kettering Cancer Center; Babak J. Mehrara, Memorial Sloan Kettering Cancer Center
• Language: English
• Date: 2018-05-17
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-04418-y
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 9
• Issue: 1
• Start Page: 1970
• End Page: 1970
• Grant/Funding Information: This work was supported by the following: NIH R01 HL111130-01 and R21-CA194882 grants awarded to B.J.M., Sharp Foundation Fund philanthropic gift awarded to B.J.M., NIH T32 CA009501-27 grant to G.D.G.N., NIH T32 CA9501-29 grant to C.L.L., NIH T32 CA009685-21A1 grant to D.A.C., Plastic Surgery Foundation pilot grant 350627 to G.D.G.N., and Plastic Surgery Foundation pilot grant 312436 to J.C.G.
• Keywords: MULTIPLE-SCLEROSIS; Science & Technology - Other Topics; IN-VIVO; MACROPHAGES; WOUND REPAIR; SECONDARY LYMPHEDEMA; INFLAMMATION; Science & Technology; FIBROSIS; VEGF-C; Multidisciplinary Sciences; LYMPHANGIOGENESIS; NITRIC-OXIDE
• Research Categories: Biology, Cell

Abstract

T cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4+ T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4+ T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.