TY - JOUR
T1 - NCR+ ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice
AU - Mikami, Yohei
AU - Scarno, Gianluca
AU - Zitti, Beatrice
AU - Shih, Han Yu
AU - Kanno, Yuka
AU - Santoni, Angela
AU - O'Shea, John J.
AU - Sciumè, Giuseppe
N1 - Funding Information:
Acknowledgements: Y.M. contributed to experimental design, performed, analyzed and interpreted all the experiments, and helped to write the manuscript. G.Sca., B.Z., H.Y.S. helped with performing experiments. Y.K., A.S., and J.J.O.S. contributed to the experimental design and data interpretation, made helpful suggestions and helped to write the manuscript. G.Sci. designed, performed, analyzed, and interpreted all the experiments, conceived the project and wrote the manuscript. We thank J Simone, J Lay, K Tinsley (Flow Cytometry Section, NIAMS), G. Gutierrez-Cruz, S. Dell’Orso (NIAMS Sequencing Facility), Sun HW, Brooks SR (Biodata Mining and Discovery Section, NIAMS), and the NIAMS LACU staff for technical support. This work was supported by the Intramural Research Programs of NIAMS (to J.J.O.S.); Insti-tut Pasteur, PTR 113–17 (to G.Sci. and A.S.); Italian Association for Cancer Research (AIRC) Special Program Molecular and Clinical Oncology-5 per Mille (A.S.); the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH (Y.M.).
Funding Information:
Y.M. contributed to experimental design, performed, analyzed and interpreted all the experiments, and helped to write the manuscript. G.Sca., B.Z., H.Y.S. helped with performing experiments. Y.K., A.S., and J.J.O.S. contributed to the experimental design and data interpretation, made helpful suggestions and helped to write the manuscript. G.Sci. designed, performed, analyzed, and interpreted all the experiments, conceived the project and wrote the manuscript. We thank J Simone, J Lay, K Tinsley (Flow Cytometry Section, NIAMS), G. Gutierrez-Cruz, S. Dell'Orso (NIAMS Sequencing Facility), Sun HW, Brooks SR (Biodata Mining and Discovery Section, NIAMS), and the NIAMS LACU staff for technical support. This work was supported by the Intramural Research Programs of NIAMS (to J.J.O.S.); Institut Pasteur, PTR 113?17 (to G.Sci. and A.S.); Italian Association for Cancer Research (AIRC) Special Program Molecular and Clinical Oncology-5 per Mille (A.S.); the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH (Y.M.).
Publisher Copyright:
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/7
Y1 - 2018/7
N2 - Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We observed that NCR+ ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.
AB - Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We observed that NCR+ ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.
KW - IFN-γ
KW - Innate lymphoid cells
KW - Mucosal immunology
KW - STAT4
KW - Transcriptome
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U2 - 10.1002/eji.201847480
DO - 10.1002/eji.201847480
M3 - Article
C2 - 29524223
AN - SCOPUS:85045264529
VL - 48
SP - 1174
EP - 1180
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 7
ER -