Publikation
Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility
Wissenschaftlicher Artikel/Review - 02.02.2016
Takeda Akira, Scandella Elke, Ludewig Burkhard, Ishii Satoshi, Aoki Junken, Suematsu Makoto, Ishii Masaru, Takeda Kiyoshi, Jalkanen Sirpa, Miyasaka Masayuki, Kikuta Junichi, Hayasaka Haruko, Kobayashi Daichi, Aoi Keita, Sasaki Naoko, Sugiura Yuki, Igarashi Hidemitsu, Tohya Kazuo, Inoue Asuka, Hata Erina, Akahoshi Noriyuki, Umemoto Eiji
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Lymph nodes (LNs) are highly confined environments with a cell-dense three-dimensional meshwork, in which lymphocyte migration is regulated by intracellular contractile proteins. However, the molecular cues directing intranodal cell migration remain poorly characterized. Here we demonstrate that lysophosphatidic acid (LPA) produced by LN fibroblastic reticular cells (FRCs) acts locally to LPA2 to induce T-cell motility. In vivo, either specific ablation of LPA-producing ectoenzyme autotaxin in FRCs or LPA2 deficiency in T cells markedly decreased intranodal T cell motility, and FRC-derived LPA critically affected the LPA2-dependent T-cell motility. In vitro, LPA activated the small GTPase RhoA in T cells and limited T-cell adhesion to the underlying substrate via LPA2. The LPA-LPA2 axis also enhanced T-cell migration through narrow pores in a three-dimensional environment, in a ROCK-myosin II-dependent manner. These results strongly suggest that FRC-derived LPA serves as a cell-extrinsic factor that optimizes T-cell movement through the densely packed LN reticular network.