Regulation of Interleukin (IL)-18 Receptor Chain Expression on CD4 T Cells during T Helper (Th)1/Th2 Differentiation: Critical Downregulatory Role of IL-4 Ronald B. Smeltz,1 June Chen,1, 2 Jane Hu-Li,1 and Ethan M. Shevach1 1Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 2Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814 Abstract Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL- 12–mediated interferon (IFN)- 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 chain (IL-18R ) expression. The majority of peripheral CD4 T cells constitutively expressed the IL-18R . Upon antigen stim- ulation in the presence of IL-12, marked enhancement of IL-18R expression was observed. IL-12–mediated upregulation of IL-18R required IFN- . Activated CD4 T cells that ex- pressed low levels of IL-18R could produce IFN- when stimulated with the combination of IL-12 and IL-18, while CD4 cells which expressed high levels of IL-18R could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18R expression. Both IL-4 / and signal transducer and activator of transcription (Stat)6 / T cells expressed higher levels of IL-18R after TCR stimulation. Furthermore, ac- tivated T cells from Stat6 / mice produced more IFN- in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18R by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response. Key words: IFN- –inducing factor • IL-12 • IL-1R–related protein • Stat • IFN- Introduction IL-18 is an 18-kD cytokine originally described as IFN- –inducing factor for its ability to augment IFN- pro- duction by activated T cells (1). Subsequently, IL-18 has been regarded as a proinflammatory cytokine that can syn- ergize with IL-12 to increase IFN- production, NK cell cytotoxicity, and Th1 responses (2–5). While IL-18 clearly enhances Th1 responses, it is less clear whether IL- 18 is capable of initiating Th1 differentiation in the ab- sence of IL-12 (6–10). Although a majority of published reports link IL-18 with Th1-associated functions, IL-18 has recently been shown to augment Th2 responses (11– 14). Administration of IL-18 to mice led to an increase in IL-4 production and elevated serum IgE. The mechanisms whereby IL-18 can influence both Th1 and Th2 responses are unclear at this time. The IL-18R complex is composed of two known chains, IL-18 receptor chain (IL-18R )* and IL-18R (15–20). IL-18R (IL-1R5) was originally described as IL-1 receptor-related protein (IL-1Rrp) because of its homol- ogy with the IL-1/Toll receptor family and is the extracel- lular binding domain of the IL-18R complex. IL-18R (also known as IL-18RAcPL or IL-1R7) is the signal trans- ducing chain of the IL-18R complex and is also a member of the IL-1R family. It has been widely believed that the IL-18R is not expressed on naive T cells, but is induced during differentiation of Th1, but not Th2, cells. Here, we have used a recently developed polyclonal antibody to IL- 18R to investigate regulation of its expression on differ- entiating CD4 T cells. In contrast to previous studies, we demonstrate that resting peripheral CD4 and CD8 T Address correspondence to Ethan M. Shevach, National Institutes of Health, Bldg. 10, Rm. 11N315, Bethesda, MD 20892. Phone: 301-496- 6449; Fax: 301-496-0222; E-mail: ems1@mail.nih.gov *Abbreviations used in this paper: IL-18R , IL-18 receptor chain; MFI, mean fluorescence intensity; NMS, normal mouse serum; RAG, recombi- nation activating gene; Stat, signal transducer and activator of transcription. 143 The Journal of Experimental Medicine • Volume 194, Number 2, July 16, 2001 143–153 http://www.jem.org/cgi/content/full/194/2/143