Tristetraprolin regulates CD8 T cell functions and antitumor immunity through targeting IL-12 family cytokines

Abstract

Abstract IFN-γ-producing CD8+T cells (CTLs) are essential for host defense against viral infection and cancer. The mechanisms that regulate the development and function of CTLs still remain largely elusive. Tristetraprolin (TTP) is an RNA-binding protein that promotes decay of the mRNAs encoding cytokines produced in macrophages. We recently found that CD8T cells of TTP deficient mice showed effector phenotype and produced more IFN-γ than CD8 T cells of WT mice. When isolated naïve CD8 T cells were activated in vitro, however, IFN-γ production by WT and Zfp36−/−CD8 T cells was comparable. We found that the levels of IL-27 and IL-12 in serum were increased in Zfp36−/− mice compared to WT mice both at the resting state and after LPS challenge. Macrophages deficient of TTP produced more IL-27 and IL-12. Furthermore, we discovered that TTP inhibited IL-27 by promoting p28 mRNA degradation whereas suppressed IL-12 by affecting NF-kB signaling. Deletion of IL-27 receptor WSX-1 in Zfp36−/−mice (WSX-1/TTP double KO) led to a reduction in CTLs. In a murine mammary gland tumor model, tumor growth was suppressed in Zfp36−/−mice, and this suppression was almost completely abolished in the WSX-1/TTPdouble KO mice and after depleting CD8 T cells. Our study unveils a novel regulatory pathway for CTL function and antitumor immunity regulation mediated by TTP.