biostudies-literatureStehle CDeutsche ForschungsgemeinschaftThe state of Berlin and the “European Regional Development Fund”Dr. Rolf M. Schwiete FoundationLeibniz-GemeinschaftWellcome Trust1231-1244https://www.ebi.ac.uk/biostudies/studies/S-EPMC7614953biostudies-literatureUnknown22(10)The generation of lymphoid tissues during embryogenesis relies on group 3 innate lymphoid cells (ILC3) displaying lymphoid tissue inducer (LTi) activity and expressing the master transcription factor RORγt. Accordingly, RORγt-deficient mice lack ILC3 and lymphoid structures, including lymph nodes (LN). Whereas T-bet affects differentiation and functions of ILC3 postnatally, the role of T-bet in regulating fetal ILC3 and LN formation remains completely unknown. Using multiple mouse models and single-cell analyses of fetal ILCs and ILC progenitors (ILCP), here we identify a key role for T-bet during embryogenesis and show that its deficiency rescues LN formation in RORγt-deficient mice. Mechanistically, T-bet deletion skews the differentiation fate of fetal ILCs and promotes the accumulationNature immunologyT-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation.PMC7614953TRR130, TP17INST 335/597-1 FUGGRO3565/2-1RO3565/1-1TRR241 B02110199110199/Z/15/ZK259/2019DFG-SFB TRR241 B03SPP1937 (HA5354/8-1 and 8-2)Withers DRMashreghi MFFinke DRomagnani CRuckert THauser AEZimmermann JDurek PGajdasik DWFiancette RStehle CUlbricht CWillis CChang HDfalseT-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation.The generation of lymphoid tissues during embryogenesis relies on group 3 innate lymphoid cells (ILC3) displaying lymphoid tissue inducer (LTi) activity and expressing the master transcription factor RORγt. Accordingly, RORγt-deficient mice lack ILC3 and lymphoid structures, including lymph nodes (LN). Whereas T-bet affects differentiation and functions of ILC3 postnatally, the role of T-bet in regulating fetal ILC3 and LN formation remains completely unknown. Using multiple mouse models and single-cell analyses of fetal ILCs and ILC progenitors (ILCP), here we identify a key role for T-bet during embryogenesis and show that its deficiency rescues LN formation in RORγt-deficient mice. Mechanistically, T-bet deletion skews the differentiation fate of fetal ILCs and promotes the accumulation2021-01-01T00:00:00Z2021 Oct2025-04-18T22:31:35.202Z2025-04-07T10:13:56.122ZS-EPMC76149533455688710.1038/s41590-021-01029-6