Prostaglandin E2 impairs CD4+ T cell activation by inhibition of Ick.: Implications in Hodgkin's lymphoma

Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E-2 (PGE(2)), a known inhibitor of CD4(+) T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4(+) Tcells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of 1ck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4(+) T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4(+) T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE2 in T cells from healthy individuals. These data strongly suggest that PGE2 is an important factor leading to CD4(+) T cell impairment observed in Hodgkin's lymphoma.