PD-1 regulates ILC3-driven intestinal immunity and homeostasis
- Author(s)
- 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;
- Journal Title
- Mucosal Immunology
- Publication Type
- Mar 14 pub ahead of print
- 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 RNAseq 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(+) ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid and polyamine synthesis associated with augmented proliferation compared with their PD-1(-) counterparts. Further, PD-1(+) ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species (ROS). 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 NCR(-) 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.
- Keywords
- Programmed cell death-1; immune protection; inflammation; intestinal homeostasis; type 3 innate lymphoid cells
- Research Division(s)
- Immunology; Advanced Technology And Biology
- PubMed ID
- 38492744
- Publisher's Version
- https://doi.org/10.1016/j.mucimm.2024.03.002
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-03-18 02:11:30
Last Modified: 2024-03-18 02:13:57