Altered expression and functional profile of lysophosphatidic acid receptors in mitogen‐activated human blood T lymphocytes

Abstract

Lysophosphatidic acid (LPA) from platelets and mononuclear phagocytes regulates T cell functions through endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs). Human blood unactivated CD4+ T cells express predominant ly Edg-4 LPA R over marginal levels of Edg-2 LPA R, as assessed by semiquantitative PCR and Western blots. After mitogen activation, the CD4+ T cells express Ed g-2 Rs at approximately one half the level of Edg-4 Rs. Secretion of IL-2 by unactivated Edg-4 R-predominant CD4+ T cells incubated with anti-CD3 plus anti-CD28 antibodies was suppressed significantly and by up to 60% by 10-10 M to 10-6 M LPA, whereas secretion of IL-2 by mitogen-activated Edg-2 R and Edg-4 R codominant CD4+ T cells was enhanced by up to twofold by the same concentrations of LPA. The possibility that the two Edg Rs transduce different LPA signals to CD4+ T cells was supported by findings that IL-2 secretion was inhibited by mouse anti-Edg-4 R monoclonal antibody, but enhanced by mouse anti-Edg-2 R monoclonal antibody. The separate effects of each LPA R were studied in Jurkat T cell transfectants expressing principally human Edg-2 Rs (Jurkat-T-2) or Edg-4 Rs (Jurkat-T-4) and stimulated with anti-CD3 plus phorbol myristate acetate. LPA and anti-Edg-4 R antibody suppressed IL-2 secretion by stimulated Jurkat-T-4 cells, whereas LPA and anti-Edg-2 R antibody enhanced IL-2 secretion by stimulated Jurkat-T-2 cells. Activation-induced alterations in the relative levels of Edg-2 and -4 Rs on CD4+ T cells thus reverse the effects of LPA on T cell receptor-stimulated generation of IL-2.

Protein Kinase C ϵ Dependence of the Recovery from Down-regulation of S1P1 G Protein-coupled Receptors of T Lymphocytes

“…Quantification of Migration of Mouse CD4 T Cells-Migration of mouse purified CD4 T cells was analyzed in Transwell chambers (Costar, Cambridge, MA) with human type IV collagen (Sigma)-coated 5-m pore width polycarbonate filters and incubation for 4 h, as described previously (6). T cell suspensions were 1 ϫ 10 7 /ml in RPMI 1640 with 5% heated and charcoal-extracted fetal bovine serum, from which 0.1 ml portions of each were loaded into top compartments of chemotactic chambers.…”

“…Stimulated mononuclear phagocytes and platelets are the predominant sources of S1P and LPA in the immune system. Blood and lymphoid tissue CD4 and CD8 T cells, B cells, and mononuclear phagocytes all express S1P and LPA GPCRs, in cell type-specific patterns, which are regulated distinctively by their respective ligands and by cellular immune activation (5)(6)(7)(8).…”

LPAR2 (lysophosphatidic acid receptor 2)

“…The expression of LPA2 has also been noted in freshly isolated human blood CD4+ T cells, B cells, and Jurkat T cells (Zheng et al, 2000;Goetzl et al, 2000;Rubenfeld et al, 2006) as well as monocyte-derived dendritic cells (Chen et al, 2006;Oz-Arslan et al, 2006). Interestingly, Zheng et al reported that LPA2 expression decreases in PMAactivated CD4+ T cells, while others reported increased expression of LPA2 after T cell activation, hence future studies are needed to dissect the expression of LPA2 during the activation of T cells (Zheng et al, 2000;Rubenfeld et al, 2006). LPA2 is also expressed on the apical surface of intestinal epithelial cells (Li et al, 2005) and in the airway epithelia cells of human lung tissue (Barekzi et al, 2006).…”

“…Human: LPA2 mRNA is expressed in a variety of tissues including human testis, leukocytes, prostate, spleen, thymus, pancreas, and bone marrow (An et al, 1998;Fang et al, 2002). The expression of LPA2 has also been noted in freshly isolated human blood CD4+ T cells, B cells, and Jurkat T cells (Zheng et al, 2000;Goetzl et al, 2000;Rubenfeld et al, 2006) as well as monocyte-derived dendritic cells (Chen et al, 2006;Oz-Arslan et al, 2006). Interestingly, Zheng et al reported that LPA2 expression decreases in PMAactivated CD4+ T cells, while others reported increased expression of LPA2 after T cell activation, hence future studies are needed to dissect the expression of LPA2 during the activation of T cells (Zheng et al, 2000;Rubenfeld et al, 2006).…”

Lysophosphatidic acid induces human natural killer cell chemotaxis and intracellular calcium mobilization

“…The activities of these two lipids for lymphoid cells have not been examined in great details. Zheng et al [26] described the presence of LPA 1 and LPA 2 in resting and PHA-activated human T cells. Also, they showed that naive T cells expressing LPA 2 do not secrete IL-2 but are capable of migrating, whereas activated T cells expressing LPA 1 do not migrate but are capable of secreting IL-2.…”