REGULATION OF THE INTERLEUKIN (IL)-12R BETA-2-SUBUNIT EXPRESSION IN DEVELOPING T-HELPER-1 (TH1) AND TH2 CELLS

The developmental commitment to a T helper 1 (Th1)- or Th2-type respon se can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells resu lts from a selective loss of IL-12 receptor (IL-12R) beta 2 subunit ex pression. To determine the basis for this selective loss, we examined IL-12R beta 2 subunit expression during Th cell development in respons e to T cell treatment with different cytokines. IL-12R beta 2 is not e xpressed by naive resting CD4(+) T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-gamm a were found to significantly modify IL-12 receptor beta 2 expression after T cell activation. IL-4 inhibited IL-12R beta 2 expression leadi ng to the loss of IL-12 signaling, providing an important point of reg ulation to promote commitment to the Th2 pathway. IFN-gamma treatment of early developing Th2 cells maintained IL-12R beta 2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-gamma production. Thus , IFN-gamma may prevent early Th cells from premature commitment to th e Th2 pathway. Controlling the expression of the IL-12R beta 2 subunit could be an important therapeutic target for the redirection of ongoi ng Th cell responses.