Differentiation of naive human CD4+ T cells into Th2 cells: The role of prostaglandin E2

T-helper (Th) 2 cells, which produce interleukin (IL)-4, IL-5, IL-10 and IL-13 upon stimulation of their T cell receptors, play an important role in the development of human allergic diseases. However, the precise mechanism involved in the differentiation of Th2 cells is not well understood compared with that of Th1 cells. The selective differentiation of Th1 or Th2 subsets is established during priming under the influence of a variety of factors. Prostaglandin E₂ (PGE₂) is one of those factors. Prostaglandin E₂ produced by antigen presenting cells directly affects the naive CD4⁺ T cells, causing them to differentiate into Th2 cells. This effect is mediated by the elevation of cyclic adenosine monophosphate (cAMP) at the early stage of T cell activation. IL-4 and PGE₂ lead naive CD4⁺ T cells to differentiate into Th2 cells cooperatively, by distinct signal transduction. Both PGE2 and IL-4 inhibit the hypomethylation of the proximal regulatory regions of the genomic IFN-γ gene, whose hypomethylation has been suggested as being important for the IFN-γ production by CD4⁺ T cells stimulated through their antigen receptors. Prostaglandin E₂ facilitates Th2 differentiation of naive CD4⁺ T cells by acting not only on T cells directly but also on antigen presenting cells by inhibiting their IL-12 production. The production of PGE₂ by monocytes is increased significantly in allergic patients. These results, taken collectively, suggest that PGE₂ plays an important role in facilitating the differentiation of Th2 cells in vivo.