Lysophospholipid Enhancement of Human T Cell Sensitivity to Diphtheria Toxin by Increased Expression of Heparin‐Binding Epidermal Growth Factor

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Abstract
The effects of lysophosphatidic acid (LPA) and sphingosine 1–phosphate (S1P) on T cell expression of heparin‐binding epidermal growth factor–like growth factor (HB‐EGF), the diphtheria toxin (DT) receptor, were investigated in the Tsup‐1 cultured line of human CD4+ 8+ 3low T lymphoblastoma cells. Tsup‐1 cells bear endothelial differentiation gene (edg)‐2 and ‐4‐encoded G protein–coupled receptors (GPCRs) for LPA and Edg‐3 and ‐5 GPCRs for S1P. Suppression by DT of Tsup‐1 cell protein synthesis was enhanced by LPA and S1P, with lipid structural specificity similar to that required for their recognition by Edg receptors. LPA and S1P increased the Tsup‐1 cell level of immunoreactive HB‐EGF, and neutralizing antibodies to HB‐EGF inhibited LPA and S1P enhancement of Tsup‐1 cell susceptibility to DT. Stabilized transfection of Tsup‐1 cells with a combination of plasmids encoding Edg‐2 plus ‐4 antisense mRNA suppressed the levels of Edg‐2 and ‐4, but not Edg‐3 and ‐5, in Western blots and reduced in parallel the increments in HB‐EGF and susceptibility to DT evoked by LPA but not S1P. Similar transfection with Edg‐3 plus ‐5 antisense plasmids suppressed Tsup‐1 cell levels of immunoreactive Edg‐3 and ‐5, but not Edg‐2 or ‐4, and concurrently reduced S1P‐, but not LPA‐, induced Tsup‐1 cell increases in both HB‐EGF and susceptibility to DT. Edg GPCR‐mediated LPA and S1P enhancement of T cell sensitivity to DT, thus, may be attributable to increased expression of the DT receptor HB‐EGF.

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