Abstract Environmental and molecular cues early in life are often associated with the permanent shaping of our immune system during adulthood. Although increasing, our knowledge of the signaling pathways that operate in early life and their temporal mode of action is limited. Herein, we demonstrate that the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), which are E3 ubiquitin ligases and master regulators of the nuclear factor-kappa B (NF-κB) pathway, function during late neonatal and prepubescent life to sustain interleukin(IL)-17-producing gamma delta T cells (γδT17) and group 3 innate lymphoid cells (ILC3). We show that cell-intrinsic deficiency in cIAP1/2 at 3-4 weeks of life leads to downregulation of the transcription factors cMAF and RORγt, and failure to enter cytokine-induced cell cycle. This is followed by progressive loss of γδT17 cells and ILC3 while mice are aging. Mice deficient in cIAP1/2 have severely reduced γδT17 cells and ILC3, present with suboptimal γδT17 responses in the skin, lack small 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-κB pathway. Our data identify the cIAP E3 ubiquitin ligases as critical early life molecular switches for establishing effective type-3 immunity during aging.

The cIAP ubiquitin ligases sustain type 3 γδ T and innate lymphoid cells during aging to allow normal cutaneous and mucosal responses