The ZFP36 family of RNA-binding proteins regulate homeostatic and autoreactive T cell responses

Abstract The zinc finger 36 (ZFP36) family of RNA-binding proteins, consisting of ZFP36, ZFP36L1, and ZFP36L2, is known to negatively regulate mRNA stability and/or inhibit translation of many transcripts, including cytokines. While there are reports of all three family members regulating T cell cytokine production, delineating the functions of these genes is challenging due to spontaneous phenotypes 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 paired deletions, do mice spontaneously develop an inflammatory disease characterized by early lethality, hypercytokinemia, and immune cell infiltration into some peripheral organs, including the central nervous system. As SNPs in human ZFP36L1 and ZFP36L2 have been linked to susceptibility for multiple sclerosis, we tested ZFP36 family member individual and paired T cell-deficient mice in experimental autoimmune encephalomyelitis (EAE). To our surprise, Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice were markedly protected from EAE clinical disease, while no change in disease severity was seen with any deletion strains involving Zfp36. There was a severe impairment in generating antigen-specific CD4+ T cells in Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice during EAE priming. Our findings demonstrate a novel redundancy of the ZFP family members in regulating T cell homeostasis and a shared role for ZFP36L1 and ZFP36L2 to promote clonal expansion. Understanding the individual and shared functions of the ZFP36 family members may lead to opportunities to target them to suppress T cell-driven autoimmunity. M.E.C. supported by the National Science Foundation Graduate Research Fellowship program (DGE-1745038) and by grant 5T32AI007163 from the NIAID. B.T.E. supported by the NIAID (R01 AI113118).