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mTOR-Mediated Regulation of Group 3 Innate Lymphoid Cell Numbers and Cytokine Responses

Teufel, Claudia Cornelia. mTOR-Mediated Regulation of Group 3 Innate Lymphoid Cell Numbers and Cytokine Responses. 2020, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Group 3 innate lymphoid cells (ILC3s) are most abundant at surface barrier regions, particularly in the mucosa of the intestinal tract. ILC3 subsets produce various cytokines under homeostatic and activating conditions and act as inducers of lymphoid tissue development. ILC3-derived IL-22 contributes to tissue homeostasis, tissue repair and protection against infections. On the other hand, ILC3-mediated IFN-g responses participate in the pathogenesis of intestinal inflammatory diseases. It is not fully understood which molecular pathways regulate the protective versus the pathogenic outcome of ILC3 immune responses in the intestine.
Mechanistic target of rapamycin complexes (mTORC) 1 and 2 integrate activation signals and environmental cues, drive activation-induced metabolic adaptation and shape immune responses by regulating proliferation, differentiation and cytokine responses. Results obtained in T cells demonstrate that mTOR signaling incorporates cues from various sources including nutrient-, cell- and microbiota-derived metabolites and critically affects cell function. Given the known impact of these factors on the generation, differentiation and function of ILC3s, I hypothesized that mTORC1 and/or mTORC2 are critical regulators of ILC3 differentiation and function. To investigate the impact of mTOR signaling on ILC3s, I generated wildtype and Rag2-/- lymphopenic mouse strains with a conditional RORc promoter-driven deletion of Rptor and/or Rictor, the essential subunits of mTORC1 and mTORC2, respectively.
mTORC1 and mTORC2 had a tissue-specific impact on ILC3 development and proliferation. Whereas small intestinal ILC3s required mTORC1 and to a lesser extent mTORC2, maintenance of colonic ILC3 numbers was independent of mTOR signaling. Small intestinal ILC3s from Rag2-/- mice exhibited a higher dependency on both mTORCs than small intestinal ILC3s from wildtype mice, indicating that mTOR is differentially regulated in ILC3s from lymphopenic and wildtype mice. Rptor- and Rictor-deficient ILC3s displayed significantly impaired IL-23/IL-1b-mediated IFN-g production, while IL-22 production was only marginally affected. Consistently, Rag2-/- mice with ILC3-specific deletion of Rptor or Rictor were more resistant to IFN-g-dependent a-CD40 colitis, but exhibited no obvious defects in IL-22-mediated defense against Citrobacter rodentium infection. Taken together, those findings suggest that mTORC1 and mTORC2 signaling occupy a critical role in IFN-g production of ILC3s in vitro and in vivo and thus represent central regulators of protective versus inflammatory responses in the intestine. This implies that therapeutic mTOR blockade may have beneficial effects in colitis patients by downmodulating the IFN-g response of ILC3s.
Advisors:Finke, Daniela and Pieters, Jean and Müller, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Molekulare Medizin in der Pädiatrie (Finke)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Molekulare Medizin in der Pädiatrie (Finke)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Developmental Immunology (Finke)
UniBasel Contributors:Finke, Daniela and Pieters, Jean
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13778
Thesis status:Complete
Number of Pages:159
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss137784
edoc DOI:
Last Modified:15 Feb 2021 11:45
Deposited On:27 Jan 2021 14:29

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