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

doi:10.1016/j.celrep.2024.114948

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^*

^*Corresponding author for this work

Inflammation Biology

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Abstract

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.

Original language	English
Article number	114948
Pages (from-to)	114948
Journal	Cell Reports
Volume	43
Issue number	12
Early online date	23 Nov 2024
DOIs	https://doi.org/10.1016/j.celrep.2024.114948 https://doi.org/10.1016/j.celrep.2024.114948
Publication status	Published - Dec 2024

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IFN-γ-dependent regulation of intestinal_LEBRUSANTFERNANDEZ_Publishedonline23November2024_GOLD_VoR (CC BY)Final published version, 5.83 MBLicence: CC BY

https://linkinghub.elsevier.com/retrieve/pii/S2211124724012993

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title = "IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells",

abstract = "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.",

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AU - Lebrusant-Fernandez, Marta

AU - Ap Rees, Tom

AU - Jimeno, Rebeca

AU - Angelis, Nikolaos

AU - Ng, Joseph C.

AU - Fraternali, Franca

AU - Li, Vivian S.W.

AU - Barral, Patricia

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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JO - Cell Reports

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IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells

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