Interferon-gamma and interleukin-4 regulate T cell interleukin-12 responsiveness through the differential modulation of high-affinity interleukin-12 receptor expression.
Interferon-gamma (IFN-gamma) 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-gamma 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-gamma 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-gamma is associated with the upregulation of high-affinity IL-12 receptor expression. Through the use of a newly synthesized neutralizing antibody to the low-affinity IL-12 receptor beta subunit (IL-12Rbeta), we show that neither IL-4 nor IFN-gamma affect the expression of IL-12Rbeta, 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-gamma 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-12Rbeta and required, together with IL-12Rbeta, 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.
Gollob
J A
JA
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. jared_gollob@macmailgw.dfci.harvard.edu
Kawasaki
H
H
Ritz
J
J
D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D008213:Lymphocyte Activation; D018123:Receptors, Interleukin / Q000502:physiology*; D053707:Receptors, Interleukin-12; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells; D018418:Th2 Cells; D015854:Up-Regulation
D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma