Interferon‐γ and interleukin‐4 regulate T cell interleukin‐12 responsiveness through the differential modulation of high‐affinity interleukin‐12 receptor expression

Abstract

Interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) are mutually antagonistic cytokines that stimulate CD4⁺ T cells to develop into either Th1 or Th2 cells. One feature of Th2 differentiation in mice is the loss of IL‐12‐induced Jak2 and Stat4 activation, which is accompanied by the inability to produce IFN‐γ in response to IL‐12. In this report, we show that freshly isolated human T cells activated with phytohemagglutinin (PHA) in the presence of IL‐4 exhibit a greatly diminished response to IL‐12, whereas the IL‐12 response of T cells activated with PHA plus IFN‐γ is enhanced. Radiolabeled IL‐12 binding studies demonstrate that the impairment of T cell IL‐12 responsiveness by IL‐4 is associated with the down‐regulation of high‐affinity IL‐12 receptor expression. In contrast, the enhancement of IL‐12 responsiveness by IFN‐γ is associated with the up‐regulation of high‐affinity IL‐12 receptor expression. Through the use of a newly synthesized neutralizing antibody to the low‐affinity IL‐12 receptor β subunit (IL‐12Rβ), we show that neither IL‐4 nor IFN‐γ affect the expression of IL‐12Rβ, which we determine to be one of at least two low‐affinity subunits required for high‐affinity IL‐12 binding. These findings suggest that IL‐4 and IFN‐γ exert opposite effects on T cell IL‐12 responsiveness by differentially modulating the expression of low‐affinity IL‐12 receptor subunits that are distinct from IL‐12Rβ and required, together with IL‐12Rβ, for high‐affinity IL‐12 binding and IL‐12 responsiveness. This provides a basis for understanding the interplay between different cytokines at the level of cytokine receptor expression, and offers insight into one of the mechanisms governing Th1 and Th2 development.