Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation

Carys A. Croft, Anna Thaller, Solenne Marie, Jean-Marc Doisne, Laura Surace, Rui Yang, Anne Puel, Jacinta Bustamante, Jean-Laurent Casanova and James P. Santo ()
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Carys A. Croft: Université Paris Cité, Inserm U1223, Innate Immunity Unit
Anna Thaller: Université Paris Cité, Inserm U1223, Innate Immunity Unit
Solenne Marie: Université Paris Cité, Inserm U1223, Innate Immunity Unit
Jean-Marc Doisne: Université Paris Cité, Inserm U1223, Innate Immunity Unit
Laura Surace: Université Paris Cité, Inserm U1223, Innate Immunity Unit
Rui Yang: Rockefeller University
Anne Puel: Necker Branch, INSERM
Jacinta Bustamante: Necker Branch, INSERM
Jean-Laurent Casanova: Rockefeller University
James P. Santo: Université Paris Cité, Inserm U1223, Innate Immunity Unit

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Innate lymphoid cells (ILCs) include cytotoxic natural killer cells and distinct groups of cytokine-producing innate helper cells which participate in immune defense and promote tissue homeostasis. Circulating human ILC precursors (ILCP) able to generate all canonical ILC subsets via multi-potent or uni-potent intermediates according to our previous work. Here we show potential cooperative roles for the Notch and IL-23 signaling pathways for human ILC differentiation from blood ILCP using single cell cloning analyses and validate these findings in patient samples with rare genetic deficiencies in IL12RB1 and RORC. Mechanistically, Notch signaling promotes upregulation of the transcription factor RORC, enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions in multi-potent and uni-potent ILCP. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions but also generally suppresses ILC production from multi-potent ILCP. Our results identify a Notch->RORC- > IL-23R pathway which operates during human ILC differentiation. These observations may help guide protocols to expand functional ILC subsets in vitro with an aim towards novel ILC therapies for human disease.

Date: 2022
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DOI: 10.1038/s41467-022-32089-3

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