IL‐33 synergizes with TCR and IL‐12 signaling to promote the effector function of CD8+ T cells

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Abstract
The effector functions of CD8+ T cells are influenced by tissue inflammatory microenvironments. IL‐33, a member of the IL‐1 family, acts as a danger signal after its release during cell necrosis. The IL‐33/ST2 axis has been implicated in various Th2 responses. Its role in CD8+ T‐cell‐mediated immune response is, however, not known. Here we find that type 1 cytotoxic T (Tc1) cells cultured in vitro unexpectedly express high levels of the IL‐33 receptor ST2. Interestingly, the expression of ST2 in Tc1 cells is dependent on T‐bet, a master Th1/Tc1 transcription factor. In addition, IL‐33 enhances TCR‐triggered IFN‐γ production. IL‐33 together with IL‐12 can stimulate IFN‐γ production in Tc1 cells. Moreover, IL‐33 synergizes with IL‐12 to promote CD8+ T‐cell effector function. The synergistic effect of IL‐33 and IL‐12 is partly mediated by Gadd45b. Together, these in vitro data establish a novel role of IL‐33 in promoting effector type 1 adaptive immune responses.