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

• Published in: The Journal of experimental medicine 2023-08, Vol.220 (8)
• Main Authors: Rizk, John, Mörbe, Urs M, Agerholm, Rasmus, Baglioni, Maria Virginia, Catafal Tardos, Elisa, Fares da Silva, Marcelo Gregorio Filho, Ulmert, Isabel, Kadekar, Darshana, Viñals, Monica Torrellas, Bekiaris, Vasileios
• Format: Article
• Language: English
• Subjects: Aging; Animals; Immunity, Innate; Interleukins - metabolism; Lymphocytes; Mice; Ubiquitin
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20221534

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 γ δ T cells (γδT17) 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 RORγt and failure to enter the cell cycle, followed by progressive loss of γδT17 cells and ILC3 during aging. Mice deficient in cIAP1/2 have severely reduced γδT17 cells and ILC3, present with suboptimal γδT17 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-κB pathway. Our data identify cIAP1/2 as early-life molecular switches that establish effective type 3 immunity during aging.