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

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 LPA 2 to induce T-cell motility. In vivo, either specific ablation of LPA-producing ectoenzyme autotaxin in FRCs or LPA 2 deficiency in T cells markedly decreased intranodal T cell motility, and FRC-derived LPA critically affected the LPA 2 -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 LPA 2 . The LPA-LPA 2 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. DOI: http://dx.doi.org/10.7554/eLife.10561.001 eLife digest Small organs called lymph nodes are found throughout the body and help to filter out harmful particles and cells. Lymph nodes are packed with different types of immune cells, such as the T-cells that play a number of roles in detecting and destroying bacteria, viruses and other disease-causing microbes. Within the lymph node, T-cells crawl along a meshwork made up of cells called fibroblastic reticular cells. The T-cells appear to move in random patterns, but the signals that drive this movement remain ill-defined. Now, Takeda et al. reveal that a lipid called lysophosphatidic acid (LPA), which is produced by the fibroblastic reticular cells, is responsible for regulating how T-cells move around inside the lymph nodes. T-cells are able to detect LPA via certain receptor proteins on their surface. Takeda et al. engineered mice that were either unable to produce a particular LPA receptor on their T-cells, or that produced less LPA than normal. The T-cells of these mice moved around less than T-cells in normal mice. Further experiments revealed that LPA signaling also affects the signaling pathway that alters how well the T-cells stick to nearby surfaces. This suggests that LPA helps to optimize T-cell movement to allow the cells to navigate the small spaces found between the fibroblastic reticular cells. In the future, targeting the processes involved in LPA signaling could help to develop new treatments for disorders of the immune system. DOI: http://dx.doi.org/10.7554/eLife.10561.002