T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation

Christina Stehle; Timo Rückert; Rémi Fiancette; Dominika W. Gajdasik; Claire Willis; Carolin Ulbricht; Pawel Durek; Mir-Farzin Mashreghi; Daniela Finke; Anja erika Hauser; David R. Withers; Hyun-Dong Chang; Jakob Zimmermann; Chiara Romagnani

doi:10.1038/s41590-021-01029-6

T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation

Christina Stehle, Timo Rückert, Rémi Fiancette, Dominika W. Gajdasik, Claire Willis, Carolin Ulbricht, Pawel Durek, Mir-Farzin Mashreghi, Daniela Finke, Anja erika Hauser, David R. Withers, Hyun-Dong Chang, Jakob Zimmermann, Chiara Romagnani^*

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

Abstract

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 accumulation of PLZF^hi ILCP expressing central LTi molecules in a RORα-dependent fashion. Our data unveil an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

Original language	English
Pages (from-to)	1231–1244
Number of pages	14
Journal	Nature Immunology
Volume	22
Issue number	10
Early online date	23 Sept 2021
DOIs	https://doi.org/10.1038/s41590-021-01029-6
Publication status	Published - Oct 2021

Bibliographical note

Acknowledgements:
We thank J. Kirsch, T. Kaiser (Flow Cytometry Core Facility, Deutsches Rheuma-Forschungszentrum, Berlin) and K. Lehmann (Deutsches Rheuma-Forschungszentrum) for technical help. We thank M. Babic for precise help with detection of LN phenotypes; H.-R. Rodewald (Division for Cellular Immunology, German Cancer Research Center, Heidelberg, Germany) and J. Zhu (Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA) for providing Il7rcre and Tbx21-ZsGreen mice, respectively; A. Diefenbach and M. Hepworth for scientific discussion; G. Gasteiger, C. Klose, T. Schüler, D. Hernández, J. Zhu and A. Kruglov for critically reading the paper. Funding came from Deutsche Forschungsgemeinschaft (DFG) grants from the Heisenberg Program nos. (RO3565/1-1), RO3565/2-1, SPP 1937 (RO3565/4-1 and 4-2) to C.R., DFG-SFB TRR241 B02 to C.R and B03 to H.D.C., R.M. Schwiete Foundation to H.D.C., Leibniz-Science Campus Chronic Inflammation and Leibniz-Kooperative Exzellenz K259/2019 to C.R. and INST 335/597-1 FUGG. SPP1937 (HA5354/8-1 and 8-2) and TRR130, TP17 to A.E.H, and the state of Berlin and the ‘European Regional Development Fund’ (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum) to M-F.M.)

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Stehle, C., Rückert, T., Fiancette, R., Gajdasik, D. W., Willis, C., Ulbricht, C., Durek, P., Mashreghi, M.-F., Finke, D., Hauser, A. E., Withers, D. R., Chang, H.-D., Zimmermann, J., & Romagnani, C. (2021). T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation. Nature Immunology, 22(10), 1231–1244. https://doi.org/10.1038/s41590-021-01029-6

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title = "T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation",

abstract = "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 accumulation of PLZFhi ILCP expressing central LTi molecules in a RORα-dependent fashion. Our data unveil an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.",

author = "Christina Stehle and Timo R{\"u}ckert and R{\'e}mi Fiancette and Gajdasik, {Dominika W.} and Claire Willis and Carolin Ulbricht and Pawel Durek and Mir-Farzin Mashreghi and Daniela Finke and Hauser, {Anja erika} and Withers, {David R.} and Hyun-Dong Chang and Jakob Zimmermann and Chiara Romagnani",

note = "Acknowledgements: We thank J. Kirsch, T. Kaiser (Flow Cytometry Core Facility, Deutsches Rheuma-Forschungszentrum, Berlin) and K. Lehmann (Deutsches Rheuma-Forschungszentrum) for technical help. We thank M. Babic for precise help with detection of LN phenotypes; H.-R. Rodewald (Division for Cellular Immunology, German Cancer Research Center, Heidelberg, Germany) and J. Zhu (Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA) for providing Il7rcre and Tbx21-ZsGreen mice, respectively; A. Diefenbach and M. Hepworth for scientific discussion; G. Gasteiger, C. Klose, T. Sch{\"u}ler, D. Hern{\'a}ndez, J. Zhu and A. Kruglov for critically reading the paper. Funding came from Deutsche Forschungsgemeinschaft (DFG) grants from the Heisenberg Program nos. (RO3565/1-1), RO3565/2-1, SPP 1937 (RO3565/4-1 and 4-2) to C.R., DFG-SFB TRR241 B02 to C.R and B03 to H.D.C., R.M. Schwiete Foundation to H.D.C., Leibniz-Science Campus Chronic Inflammation and Leibniz-Kooperative Exzellenz K259/2019 to C.R. and INST 335/597-1 FUGG. SPP1937 (HA5354/8-1 and 8-2) and TRR130, TP17 to A.E.H, and the state of Berlin and the {\textquoteleft}European Regional Development Fund{\textquoteright} (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum) to M-F.M.)",

year = "2021",

month = oct,

doi = "10.1038/s41590-021-01029-6",

language = "English",

volume = "22",

pages = "1231–1244",

journal = "Nature Immunology",

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Stehle, C, Rückert, T, Fiancette, R, Gajdasik, DW, Willis, C, Ulbricht, C, Durek, P, Mashreghi, M-F, Finke, D, Hauser, AE, Withers, DR, Chang, H-D, Zimmermann, J & Romagnani, C 2021, 'T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation', Nature Immunology, vol. 22, no. 10, pp. 1231–1244. https://doi.org/10.1038/s41590-021-01029-6

TY - JOUR

T1 - T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation

AU - Stehle, Christina

AU - Rückert, Timo

AU - Fiancette, Rémi

AU - Gajdasik, Dominika W.

AU - Willis, Claire

AU - Ulbricht, Carolin

AU - Durek, Pawel

AU - Mashreghi, Mir-Farzin

AU - Finke, Daniela

AU - Hauser, Anja erika

AU - Withers, David R.

AU - Chang, Hyun-Dong

AU - Zimmermann, Jakob

AU - Romagnani, Chiara

N1 - Acknowledgements: We thank J. Kirsch, T. Kaiser (Flow Cytometry Core Facility, Deutsches Rheuma-Forschungszentrum, Berlin) and K. Lehmann (Deutsches Rheuma-Forschungszentrum) for technical help. We thank M. Babic for precise help with detection of LN phenotypes; H.-R. Rodewald (Division for Cellular Immunology, German Cancer Research Center, Heidelberg, Germany) and J. Zhu (Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA) for providing Il7rcre and Tbx21-ZsGreen mice, respectively; A. Diefenbach and M. Hepworth for scientific discussion; G. Gasteiger, C. Klose, T. Schüler, D. Hernández, J. Zhu and A. Kruglov for critically reading the paper. Funding came from Deutsche Forschungsgemeinschaft (DFG) grants from the Heisenberg Program nos. (RO3565/1-1), RO3565/2-1, SPP 1937 (RO3565/4-1 and 4-2) to C.R., DFG-SFB TRR241 B02 to C.R and B03 to H.D.C., R.M. Schwiete Foundation to H.D.C., Leibniz-Science Campus Chronic Inflammation and Leibniz-Kooperative Exzellenz K259/2019 to C.R. and INST 335/597-1 FUGG. SPP1937 (HA5354/8-1 and 8-2) and TRR130, TP17 to A.E.H, and the state of Berlin and the ‘European Regional Development Fund’ (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum) to M-F.M.)

PY - 2021/10

Y1 - 2021/10

N2 - 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 accumulation of PLZFhi ILCP expressing central LTi molecules in a RORα-dependent fashion. Our data unveil an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

AB - 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 accumulation of PLZFhi ILCP expressing central LTi molecules in a RORα-dependent fashion. Our data unveil an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

UR - http://europepmc.org/abstract/med/34556887

U2 - 10.1038/s41590-021-01029-6

DO - 10.1038/s41590-021-01029-6

M3 - Article

C2 - 34556887

SN - 1529-2908

VL - 22

SP - 1231

EP - 1244

JO - Nature Immunology

JF - Nature Immunology

IS - 10

ER -

T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation

Abstract

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