SELECTIVE EXPRESSION AND FUNCTIONS OF INTERLEUKIN-18 RECEPTOR ON T-HELPER (TH) TYPE-1 BUT NOT TH2 CELLS

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and syner gizes 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 constituti vely and consistently in long-term cultured clones, as well as on newl y polarized Th1 but not Th2 cells. IL-18 sustained the expression of I L-12R beta 2 mRNA, indicating that IL-18R transmits signals that maint ain Th1 development through the IL-12R complex. In turn, IL-12 upregul ated 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 d erived fi-om naive ovalbumin-T cell antigen receptor-alpha beta transg enic 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 i n mice. This was accompanied by shifting the balance from Th1 to Th2 r esponses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these da ta 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-1 2 and IL-18 on Th1 development may be due to the reciprocal upregulati on of their receptors. Furthermore, IL-18R is a cell surface marker di stinguishing Th1 fi-om Th2 cells and may be a therapeutic target.