Abstract
Lysophosphatidic acid (LPA) and the LPA-generating enzyme autotaxin (ATX) have been implicated in lymphocyte trafficking and the regulation of lymphocyte entry into lymph nodes. High local concentrations of LPA are thought to be present in lymph node high endothelial venules, suggesting a direct influence of LPA on cell migration. However, little is known about the mechanism of action of LPA, and more work is needed to define the expression and function of the six known G protein-coupled receptors (LPA 1–6) in T cells. We studied the effects of 18∶1 and 16∶0 LPA on naïve CD4+ T cell migration and show that LPA induces CD4+ T cell chemorepulsion in a Transwell system, and also improves the quality of non-directed migration on ICAM-1 and CCL21 coated plates. Using intravital two-photon microscopy, lpa2−/− CD4+ T cells display a striking defect in early migratory behavior at HEVs and in lymph nodes. However, later homeostatic recirculation and LPA-directed migration in vitro were unaffected by loss of lpa2. Taken together, these data highlight a previously unsuspected and non-redundant role for LPA2 in intranodal T cell motility, and suggest that specific functions of LPA may be manipulated by targeting T cell LPA receptors.
Highlights
Lymphocyte trafficking to immune organs and peripheral tissues is a highly regulated process that has emerged as a critical checkpoint in the initiation and outcome of immune responses
When lysophosphatidic acid (LPA) was added to the bottom chamber, there was no increase in migration of naıve CD4+ T cells to the bottom chamber, indicating that LPA does not induce chemotaxis (Figure 1A, second bar)
We determined whether LPA interacted with CCL21, a chemokine involved in naıve T cell homing to lymph nodes
Summary
Lymphocyte trafficking to immune organs and peripheral tissues is a highly regulated process that has emerged as a critical checkpoint in the initiation and outcome of immune responses. A current paradigm in immunology is that different lymphocyte subsets exhibit different homing properties in vivo that are regulated by chemokines, adhesion molecules, and lipid mediators. The enzyme autotaxin (ATX) has been shown to be constitutively expressed at the high endothelial venules (HEV) of lymph nodes and potentially regulate lymphocyte entry. ATX expression is independent of HEV-associated chemokines or MyD88-dependent signals, highlighting a potential unique function for ATX in the T cell homing process [3]. Emerging data point to important roles for LPA in the immune system including lymphocyte trafficking [2,3,33,34,35]
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