Zfp36 family members redundantly protect against T cell-mediated autoinflammation and premature mortality

Abstract

Abstract Cytokine production must be tightly regulated in order to prevent auto-inflammatory diseases. The zinc finger 36 (Zfp36) family of RNA-binding proteins, including Zfp36, Zfp36l1, and Zfp36l2, are known to negatively regulate mRNA stability or translation of many transcripts, including cytokines. Polymorphisms in ZFP36L1 and ZFP36L2 have been identified in GWAS studies of a variety of human autoimmune diseases, necessitating understanding the functions of these genes. While there are reports of all three family members controlling cytokine production from T cells, delineating the exact functions of these genes has been challenging due to spontaneous phenotypes or mortality upon global deletion of single genes and potential redundancy in their functions. To overcome this, we generated Cd4-Cre+ Zfp36fl/fl Zfp36l1fl/fl Zfp36l2fl/fl mice. Only upon triple deletion, but not individual or various paired deletions, do mice spontaneously develop an inflammatory disease characterized by early mortality and immune cell infiltration into various organs, including the central nervous system, kidneys, and liver. These mice have drastically elevated levels of many cytokines in their sera. Our findings demonstrate a novel redundancy of the Zfp36 family members in regulating T cell homeostasis and suppressing cytokine-driven inflammation. We are currently investigating the specific mechanisms and mRNA targets that contribute to this phenotype and whether disease is primarily driven by CD4+ or CD8+ T cells. Understanding the individual and redundant functions of the Zfp36 family members may lead to opportunities to target them for suppression of T cell-driven autoimmunity or for activating anti-tumor or anti-pathogen T cell responses.