International Immunology Advance Access originally published online on May 20, 2005
International Immunology 2005 17(6):737-747; doi:10.1093/intimm/dxh255
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Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA
1 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA
2 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
3 Present address: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095, USA
Correspondence to: C. C. W. Hughes; E-mail: cchughes{at}uci.edu
Human endothelial cells (ECs) constitutively express OX40L and co-stimulate memory CD4+ T cell proliferation that is dependent upon OX40–OX40L interaction. In vivo, OX40 prolongs T cell survival; however, an unanswered question is whether it can also prolong synthesis of proliferation-sustaining cytokines such as IL-2. Here we show that EC co-stimulation results in the secretion of T cell IL-2, IL-3 and IFN-
and that in the absence of OX40 signals synthesis largely ceases by 12–18 h, but is prolonged up to 60 h in the presence of OX40 signaling. Blocking OX40-mediated cytokine expression at later times suppresses T cell proliferation and this can be overcome by addition of exogenous IL-2. We find that OX40 signaling has discrete effects on T cell activation as it does not affect expression of IL-10, CD25, CD69 or soluble IL-2R. Also, OX40 does not appear to alter IL-2 transcription, but rather acts to stabilize a subset of cytokine mRNAs, increasing their half-lives by 3–6-fold. We further show that OX40L induces activation of p38 mitogen-activated protein kinase (MAPK) and phosphotidyl-inositol-3-kinase (PI3K) in T cells, and using specific inhibitors, we find that increased mRNA half-life is dependent upon both these pathways but is independent of c-jun-N-terminal kinase (JNK). Thus, EC co-stimulation through OX40 leads to prolonged T cell cytokine synthesis and enhanced proliferation.
Keywords: Inflammation, memory, signal transduction
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