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PD-1 regulates ILC3-driven intestinal immunity and homeostasis.

Authors :
Jacquelot N
Xiong L
Cao WHJ
Huang Q
Yu H
Sayad A
Anttila CJA
Baldwin TM
Hickey PF
Amann-Zalcenstein D
Ohashi PS
Nutt SL
Belz GT
Seillet C
Source :
Mucosal immunology [Mucosal Immunol] 2024 Jun; Vol. 17 (3), pp. 371-386. Date of Electronic Publication: 2024 Mar 16.
Publication Year :
2024

Abstract

Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1 <superscript>+</superscript> ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid, and polyamine synthesis associated with augmented proliferation compared with their PD-1 <superscript>-</superscript> counterparts. Further, PD-1 <superscript>+</superscript> ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species. Loss of PD-1 signaling in ILC3 led to reduced IL-22 production in a cell-intrinsic manner. During inflammation, PD-1 expression was increased on natural cytotoxicity receptor (NCR) <superscript>-</superscript> ILC3 while deficiency in PD-1 expression resulted in increased susceptibility to experimental colitis and failure to maintain gut barrier integrity. Collectively, our findings uncover a new function of the PD-1 and highlight the role of PD-1 signaling in the maintenance of gut homeostasis mediated by ILC3 in mice.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1935-3456
Volume :
17
Issue :
3
Database :
MEDLINE
Journal :
Mucosal immunology
Publication Type :
Academic Journal
Accession number :
38492744
Full Text :
https://doi.org/10.1016/j.mucimm.2024.03.002