LPA and autotaxin regulate T cell migration and homing (P5095)

Abstract

Abstract Lysophosphatidic acid (LPA) has been suggested to regulate lymphocyte entry into lymph nodes because autotaxin (ATX), the enzyme that generates LPA, is constitutively expressed by lymph node high endothelial venules. However very little is known about the effects of LPA on T cell migration and homing. We studied the effects of LPA (16:0 and 18:1, 1-10 µM) on naïve mouse CD4+ T cells. Using chemotaxis assays, we found that LPA induces CD4+ T cell chemorepulsion (1.5±0.5 fold migration away from 1 µM LPA, n=26, p <0.0001) but not chemotaxis. In addition, we found that LPA increases the quality of naïve CD4+ T cell migration on ICAM-1/CCL21 coated plates as shown by increased track length, displacement, and velocity of cells in the presence of LPA (p<0.001). We next investigated the expression of LPA receptor mRNA on resting and anti-CD3/CD28 activated CD4+ T cells using qRT-PCR. We found that LPA2, LPA5, and LPA6 are highly expressed on naïve CD4+ T cells, and the expression of these decreases over the course of cell activation. In preliminary adoptive transfer experiments using gene-targeted mouse models, we found that LPA2 deficiency does not inhibit the recovery of transferred CD4+ cells from recipient lymph nodes after 42 hours, whereas fewer wild-type CD4+ cells were recovered from autotaxin-deficient mice (ATX+/-) compared to wild-type controls. Our results have uncovered previously unsuspected roles for LPA and autotaxin in regulating T cell migration and homing.