IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells
Marta Lebrusant-Fernandez,
Tom ap Rees,
Rebeca Jimeno,
Nikolaos Angelis,
Joseph C. Ng,
Franca Fraternali,
Vivian S.W. Li,
Patricia Barral
Affiliations
Marta Lebrusant-Fernandez
Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King’s College London, London, UK; The Francis Crick Institute, London, UK
Tom ap Rees
Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King’s College London, London, UK; The Francis Crick Institute, London, UK
Rebeca Jimeno
Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King’s College London, London, UK; The Francis Crick Institute, London, UK
Nikolaos Angelis
The Francis Crick Institute, London, UK
Joseph C. Ng
Randall Centre for Cell & Molecular Biophysics, King’s College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK
Franca Fraternali
Randall Centre for Cell & Molecular Biophysics, King’s College London, London, UK; Institute of Structural and Molecular Biology, University College London, London, UK
Vivian S.W. Li
The Francis Crick Institute, London, UK
Patricia Barral
Centre for Inflammation Biology and Cancer Immunology, The Peter Gorer Department of Immunobiology, King’s College London, London, UK; The Francis Crick Institute, London, UK; Corresponding author
Summary: Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis.
