The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity
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The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity. / 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.
In: Journal of Experimental Medicine, Vol. 220, No. 8, e20221534., 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity
AU - Rizk, John
AU - Mörbe, Urs M.
AU - Agerholm, Rasmus
AU - Baglioni, Maria Virginia
AU - Catafal Tardos, Elisa
AU - Fares Da Silva, Marcelo Gregorio Filho
AU - Ulmert, Isabel
AU - Kadekar, Darshana
AU - Viñals, Monica Torrellas
AU - Bekiaris, Vasileios
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1084/jem.20221534
DO - 10.1084/jem.20221534
M3 - Journal article
C2 - 37440178
VL - 220
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
SN - 0022-1007
IS - 8
M1 - e20221534.
ER -
ID: 371619243