072 The anti-inflammatory cytokine IL-37 inhibits CD4+ T cell activation through the receptor IL-1R8 and supports regulatory T cells

Abstract

IL-1 family member IL-37 inhibits both innate and adaptive immune responses. Previously, we have shown that intracellular IL-37 expression in monocytes and dendritic cells reduces inflammation and induces immune tolerance. However, the role of extracellular IL-37 on T cell activation remains unknown. Extracellularly, IL-37 has been found to form a tripartite ligand-receptor complex containing IL-1R8 (SIGIRR/TIR8) and IL-18Ra in monocytes. We used human CD4 T cells from healthy donors, transgenic mice expressing human IL-37, and the mice deficient in IL-1R8 to study the role of extracellular IL-37 on T cell activation. Treatment of human CD4+ T cells with recombinant human IL-37 reduced TCR-mediated signaling activation, T-cell proliferation, and pro-inflammatory cytokine production. Because IL-37 was highly expressed in human regulatory T (Treg) cells, we compared the effects of recombinant IL-37 in conventional T (Tconv) cells and Treg cells using human CD4+ T cells, wild-type (WT) mice, IL-37 transgenic mice, and IL-1R8-deficient mice. Recombinant IL-37 directly inhibited the canonical T-cell signaling pathways through IL-1R8 in Tconv cells, indicating a direct role of anti-inflammatory cytokine IL-37 in suppressing CD4+ Tconv cell-mediated immunity. On the other hand, recombinant IL-37 reduced Treg cell activation without affecting Treg-specific gene expression, suggesting that endogenous IL-37 expression helps Treg cells retain high levels of Treg cell gene signatures even in the presence of extracellular IL-37. IL-37’s inhibitory definition now includes a direct role in CD4+ T cell-mediated adaptive immunity.