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

• Published in: Nature communications Vol. 13; no. 1; p. 4344
• Main Authors: Croft, Carys A., Thaller, Anna, Marie, Solenne, Doisne, Jean-Marc, Surace, Laura, Yang, Rui, Puel, Anne, Bustamante, Jacinta, Casanova, Jean-Laurent, Di Santo, James P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/21; 13/31; 631/250/127/1213; 631/250/232/2058; 631/250/2502; 631/250/2504/2506; Cell Differentiation; Cloning; Cytokines; Cytotoxicity; Differentiation (biology); Effector cells; Helper cells; Homeostasis; Humanities and Social Sciences; Humans; Immune system; Immunity, Innate; Infectious diseases; Interleukin 22; Interleukin 23; Intermediates; Killer Cells, Natural; Life Sciences; Lymphocytes; Lymphoid cells; Lymphoid Progenitor Cells; Lymphoid Progenitor Cells - physiology; multidisciplinary; Mutation; Natural killer cells; Nuclear Receptor Subfamily 1, Group F, Member 3; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Precursors; Receptors, Notch; Receptors, Notch - metabolism; Roles; Science; Science (multidisciplinary); Signal transduction; Signaling; Transcription factors; Tumor necrosis factor-TNF; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32089-3

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. Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.