IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression

IL-12 is a potent inducer of IFN-gamma production and drives the developmen t of Th1 cells. Human polarized Th2 cells do not express the signaling beta 2-subunit of the IL-12R and, therefore, do not signal in response to IL-12. The question was raised as to what extent the loss of the IL-12R beta2 cha in in Th2 cells has bearing on the stability of the human Th2 phenotype. In the present report, we show that restimulation of human fully polarized Th 2 cells in the presence of IL-12 primes for a shift towards Th0/Th1 phenoty pes, accompanied by suppression of GATA-3 expression and induction of T-bet expression. These reversed cells are further characterized by a marked IL- 12R beta2 chain expression and fully restored IL-12-inducible STAT4 activat ion. The IL-12-induced phenotypic shift proved to be stable as a subsequent restimulation in the presence of IL-4 and in the absence of IL-12 could no t undo the accomplished changes. Identical results were obtained with cells from atopic patients, bath with polyclonal Th2 cell lines and allergen-spe cific Th2 cell clones. These findings suggest the possibility of restoring IL-12 responsiveness in established Th2 cells of atopic patients by stimula tion in the presence of IL-12, and that IL-12-promoting immunotherapy can b e beneficial for Th2-mediated immune disorders, targeting bath naive and me mory effector T cells.