CNOT3 maintains ILC2 integrity by destabilizing Tbx21 and Rorc mRNAs [RNA-seq]

Immune responses are initiated by activation of innate lymphoid cells (ILCs), T-bet-dependent natural killer and ILC1 cells, GATA-3-dependent ILC2 cells, and RORγt-dependent ILC3 cells. Despite accumulated knowledge of translational regulation in ILCs, comprehensive impact of mRNA decay on ILCs has not been clarified yet. CNOT3 is a main subunit of the CCR4-NOT complex which mainly destabilizes mRNAs by poly (A) deadenylation in eukaryotes. Here, we showed that CNOT3 is required for cell survival of all ILCs and that the absence of CNOT3 promoted T-bet and RORγt expression due to increased stability of Tbx21 and Rorc mRNAs in ILC2 cells and enabled them to produce granzyme B and IL-22. Likewise, Th1 and Th17 skewing was induced in CD4 T cells lacking CNOT3. Furthermore, CNOT3 in each ILC subset contributes to their type-specific immune responses. Thus, the CCR4-NOT complex controls ILC differentiation by inhibiting the potential for type 1 and 3 immunity.