Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility

Akira Takeda, Daichi Kobayashi, Keita Aoi, Naoko Sasaki, Yuki Sugiura, Hidemitsu Igarashi, Kazuo Tohya, Asuka Inoue, Erina Hata, Noriyuki Akahoshi, Haruko Hayasaka, Junichi Kikuta, Elke Scandella, Burkhard Ludewig, Satoshi Ishii, Junken Aoki, Makoto Suematsu, Masaru Ishii, Kiyoshi Takeda, Sirpa JalkanenMasayuki Miyasaka, Eiji Umemoto

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18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere10561
JournaleLife
Volume5
Issue numberFEBRUARY2016
DOIs
Publication statusPublished - 2016 Feb 2

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Takeda, A., Kobayashi, D., Aoi, K., Sasaki, N., Sugiura, Y., Igarashi, H., Tohya, K., Inoue, A., Hata, E., Akahoshi, N., Hayasaka, H., Kikuta, J., Scandella, E., Ludewig, B., Ishii, S., Aoki, J., Suematsu, M., Ishii, M., Takeda, K., ... Umemoto, E. (2016). Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility. eLife, 5(FEBRUARY2016), [e10561]. https://doi.org/10.7554/eLife.10561