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J. Exp. Med., Volume 188, Number 8, October 19, 1998 1485-1492

Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

By Damo Xu,* Woon Ling Chan,Dagger Bernard P. Leung,* David Hunter,* Kerstin Schulz,* Robert W. Carter,Dagger Iain B. McInnes,* John H. Robinson,§ and Foo Y. Liew*

From the * Department of Immunology, University of Glasgow, Glasgow G11 6NT, United Kingdom; the Dagger  Department of Virology, St. Bartholomew and Royal London School of Medicine, Queen Mary and Westfield College, University of London, London EC1A 7BE, United Kingdom; and the § Department of Immunology, University of Newcastle, Newcastle Upon Tyne NE2 4HH, United Kingdom

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta 2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alpha beta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Key words: T helper type 1 cells;  T helper type 2 cells;  interleukin 18 receptor;  inflammation;  septic shock


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