C‐maf, JunB, and Gata3 mediation of IL‐4 up‐regulation in CD4 T cells from Type 1 Sphingosine 1‐phosphate receptor (S1P1) transgenic (TG) mice

Sphingosine 1‐phosphate (S1P), derived from mast cells and platelets, regulates migration, proliferation, cytokine secretion, and other immune functions of T cells. S1P 1 and type 4 G protein‐coupled receptor for S1P (S1P 4 ) predominate in T cells, and S1P 1 alone mediates prominent regulation of T cell migration and trafficking. S1P regulates several aspects of immunity in vivo, including delayed‐type hypersensitivity and antibody production. We now investigate the effects of S1P on cytokine secretion in T cell‐selective S1P 1 TG mice. S1P specifically enhances anti‐CD3 + anti‐CD28 stimulated secretion of IL‐4 by splenic CD4 T cells of S1P 1 TG mice as quantified by ELISA, but not IL‐2 or IFN‐γ. Mean increases in IL‐4 secretion of up to 10‐fold were observed in S1P 1 TG mice, but not in wild type (WT) mice. Quantitative real time PCR analysis showed that IL‐4 mRNA in S1P 1 TG mice was up‐regulated as early as 4 hours after T cell activation in the presence of S1P. Transcription factor analysis showed that c‐maf, JunB, Gata3 protein and activity were significantly up‐regulated to a higher level in stimulated CD4 T cells from S1P 1 transgenic mice compared with WT mice. In contrast, T‐bet, FosB, C‐Fos, JunD, Fra‐1, Fra‐2, and c‐Jun all were identical in S1P 1 TG and WT mice. S1P binding to S1P 1 on CD4 T cells thus specifically induces up‐regulation of Th2‐type transcription factors c‐Maf, JunB, and Gata3, which consequently enhance IL‐4 production, leading to a Th2 phenotype. (Supported by grant HL‐31809 from the NIH)