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

RNA binding proteins are important regulators of T cell activation, proliferation, and cytokine production. The zinc finger protein 36 (ZFP36) family genes (Zfp36, Zfp36l1, and Zfp36l2) encode RNA binding proteins that promote the degradation of transcripts containing AU-rich elements. Numerous studies have demonstrated both individual and shared functions of the ZFP36 family in immune cells, but their collective function in T cells remains unclear. Here, we found a redundant and critical role for the ZFP36 proteins in regulating T cell quiescence. T cell–specific deletion of all three ZFP36 family members in mice resulted in early lethality, immune cell activation, and multiorgan pathology characterized by inflammation of the eyes, central nervous system, kidneys, and liver. Mice with T cell–specific deletion of any two Zfp36 genes were protected from this spontaneous syndrome. Triply deficient T cells overproduced proinflammatory cytokines, including IFN-γ, TNF, and GM-CSF, due to increased mRNA stability of these transcripts. Unexpectedly, T cell–specific deletion of both Zfp36l1 and Zfp36l2 rendered mice resistant to experimental autoimmune encephalomyelitits due to failed priming of antigen-specific CD4+ T cells. ZFP36L1 and ZFP36L2 double-deficient CD4+ T cells had poor proliferation during in vitro T helper cell polarization. Thus, the ZFP36 family redundantly regulates T cell quiescence at homeostasis, but ZFP36L1 and ZFP36L2 are specifically required for antigen-specific T cell clonal expansion. Description T cell homeostasis depends redundantly on the ZFP36 family of RNA binding proteins while T cell priming depends on ZFP36L1 and ZFP36L2. ZFP36 proteins: The same, but different RNA binding proteins are an essential component of the regulatory machinery that prevents excessive lymphocyte activation by limiting target transcript translation or promoting mRNA decay. Using a series of conditional knockout mice, Cook et al. systematically investigated the role of the zinc finger protein 36 (ZFP36) family of RNA binding proteins in T cell homeostasis and autoimmunity. T cell–specific deletion of all three Zfp36 genes resulted in lethal, multiorgan inflammation accompanied by excessive production of IFN-γ and TNF, whereas mice deficient in any two family members were protected. Although ZFP36 proteins were redundant in controlling T cells during homeostasis, mice with T cells lacking Zfp36l1 and Zfp36l2 were resistant to development of experimental autoimmune encephalomyelitits, demonstrating that ZFP36 family members can also perform context-specific functions during autoimmunity.