Notch signaling regulates function of human mucosal-associated invariant T (MAIT) cells
Pimpayao Sodsai,1,2 Siriwan Klinchanhom,1,2 Nattiya Hirankarn,1,2 Rangsima Reantragoon,1,2 Tanapat Palaga1,3
1 Center of Excellence in Immunology and Immune-mediated diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
2 Immunology Division, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
3 Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
Abstract
Background: Notch signaling plays an important role in the development of T lymphocytes and regulates their effector functions. The regulatory roles of Notch signaling on T cells have been intensely investigated, but whether it involves in effector functions of mucosal-associated invariant T (MAIT) cells has never been reported.
Objective: To elucidate the expression profiles of Notch receptors/ligands and to investigate their roles in human MAIT cell function.
Methods: Peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with or without anti-CD3/CD28-coupled beads, recombinant IL-12/IL-18 cytokines, riboflavin- or non-riboflavin-synthesizing bacterial cultured supernatant for 24 hours. The expression profiles of Notch receptors and ligands on MAIT cells were detected by flow cytometry. PBMCs were treated with a Notch signaling inhibitor, gamma secretase inhibitor (GSI), before stimulation to investigate the impact of interference with Notch signaling on activation and function of MAIT cells.
Results: Resting MAIT cells predominantly expressed Notch2 receptor and the ligand, Jagged 2, on their surface. Upon stimulation, MAIT cells further upregulated Notch2 and also Notch1 with its cleaved form, indicating active Notch signaling. Cytokines and cytotoxic molecules which are secreted by activated MAIT cells, were suppressed by treatment with GSI. Moreover, both TCR-dependent MAIT cell activation by microbial-derived riboflavin intermediates and TCR-independent MAIT cell activation driven by IL-18 in synergy with IL-12, were blocked by GSI treatment.
Conclusion: Notch signaling is operating in MAIT cells and is involved in their activation both in a TCR-independent and -dependent manners.
Key words: MAIT cells, Notch signaling, gamma secretase inhibitor, MAIT cell activation, MAIT cell function,