The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity

Early-life cues shape the immune system during adulthood. However, early-life signaling pathways and their temporal functions are not well understood. Herein, we demonstrate that the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), which are E3 ubiquitin ligases, sustain interleukin (IL)-17-producing & gamma; & delta; T cells (& gamma;& delta;T17) and group 3 innate lymphoid cells (ILC3) during late neonatal and prepubescent life. We show that cell-intrinsic deficiency of cIAP1/2 at 3-4 wk of life leads to downregulation of the transcription factors cMAF and ROR & gamma;t and failure to enter the cell cycle, followed by progressive loss of & gamma;& delta;T17 cells and ILC3 during aging. Mice deficient in cIAP1/2 have severely reduced & gamma;& delta;T17 cells and ILC3, present with suboptimal & gamma;& delta;T17 responses in the skin, lack intestinal isolated lymphoid follicles, and cannot control intestinal bacterial infection. Mechanistically, these effects appear to be dependent on overt activation of the non-canonical NF-& kappa;B pathway. Our data identify cIAP1/2 as early-life molecular switches that establish effective type 3 immunity during aging. Neonatal life signals shape effective adult immunity. This study shows that type 3 & gamma;& delta; T cells and ILC3 require cIAP ubiquitin ligases from late neonatal life and thereafter to fully mature, survive, and establish normal barrier immunity.