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Elife. 2016 Feb 2;5:e10561. doi: 10.7554/eLife.10561.

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

Author information

1
Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
2
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
3
MediCity Research Laboratory, University of Turku, Turku, Finland.
4
Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan.
5
Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
6
JST Precursory Research for Embryonic Science and Technology project, Saitama, Japan.
7
Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan.
8
Department of Anatomy, Kansai University of Health Sciences, Awaji, Japan.
9
Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
10
Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
11
Core Research for Evolutional Science and Technology project, Saitama, Japan.
12
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.

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.

KEYWORDS:

Fibroblastic reticular cell; Lymph node; Lymphocyte migration; Lysophospholipid; cell biology; immunology; mouse

PMID:
26830463
PMCID:
PMC4755752
DOI:
10.7554/eLife.10561
[Indexed for MEDLINE]
Free PMC Article

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