Regulation of interleukin (IL)-18 receptor alpha chain expression on CD4(+) T cells during T helper (Th)1/Th2 differentiation. Critical downregulatory role of IL-4.
Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12-mediated interferon (IFN)-gamma production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor alpha chain (IL-18Ralpha) expression. The majority of peripheral CD4(+) T cells constitutively expressed the IL-18Ralpha. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18Ralpha expression was observed. IL-12-mediated upregulation of IL-18Ralpha required IFN-gamma. Activated CD4(+) T cells that expressed low levels of IL-18Ralpha could produce IFN-gamma when stimulated with the combination of IL-12 and IL-18, while CD4(+) cells which expressed high levels of IL-18Ralpha could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18Ralpha expression. Both IL-4(-/)- and signal transducer and activator of transcription (Stat)6(-/)- T cells expressed higher levels of IL-18Ralpha after TCR stimulation. Furthermore, activated T cells from Stat6(-/)- mice produced more IFN-gamma in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18Ralpha by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.
Smeltz
R B
RB
Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Chen
J
J
Hu-Li
J
J
Shevach
E M
EM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D053727:Interleukin-18 Receptor alpha Subunit; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism*; D053724:Receptors, Interleukin-18; D050800:STAT6 Transcription Factor; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma