IL-36R ligands are potent regulators of dendritic and T cells

IL-36 alpha (IL-1F6), IL-36 beta (IL-1F8), and IL-36 gamma (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4(+) T lymphocytes constitutively express IL-36R and respond to IL-36 alpha, IL-36 beta, and IL-36 gamma. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1 beta, IL-6, TNF-alpha, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36 beta enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-gamma, IL-4, and IL-17 by CD4(+) T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100-to 1000-fold molar excess. The immunization of mice with IL-36 beta significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses. (Blood. 2011;118(22):5813-5823)