Effects of IL-36 cytokines on the regulation of early Th1 polarization. On T cell–DC interaction by TCR/MHC engagement, IL-36R, which is constitutively expressed on both DCs and Th0 cells mediates cell activation by IL-36. On one hand, IL-36 produced by epithelial cells and DCs activates DCs to secrete IL-12, and on the other hand, IL-36 produced by Th0 cells activates Th0 cells, resulting in cell proliferation, survival of naive T cells, and IL-2 secretion. By a synergistic effect, IL-36 and IL-12 induce Th1 polarization in an IL-2–dependent manner through the induction of IL-12Rβ2 expression, leading to IFN-γ secretion, which is further amplified by the proliferative effect of IL-36 on Th0 cells. The formation of a positive feedback loop created by IL-36/IL-36R leads to sustained IFN-γ–mediated immune responses.