Chronic Stress Physically Spares But Functionally Impairs Innate-Like Invariant T Cells

Long-term stress disrupts the neuroimmune interface, often resulting in immunosuppression. The deleterious effects of stress on mainstream T cells are well-documented. However, innate-like invariant T cells have been overlooked. Chief among these are invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, which fulfill important functions in anticancer and antimicrobial immunity. We found stress to surprisingly abrogate both TH1- and TH2-type responses mediated by iNKT cells. This was not due to cell death since iNKT cells were unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice triggered an abnormal response characterized by a ‘split’ inflammatory signature along with a sudden and robust induction of IL-10, IL-23 and IL-27. Pharmacological inhibitors, conditional knockout systems and gene expression analyses revealed that dysregulated iNKT cell responses were driven by iNKT cell-intrinsic glucocorticoid receptor signaling. Accordingly, the inhibitory effects of chronic stress on iNKT cell functions were lost upon habituation to predictable stressors. Importantly, iNKT cells in stressed mice failed to potentiate cytotoxicity against lymphoma targets or promote immune surveillance against metastatic melanoma. Using a congenic mouse model in which MAIT cells are abundant, these cells remained resistant to stress-induced death but demonstrated hindered TH1- and TH2-type cytokine responses, reminiscent of their iNKT cell counterparts. This was corroborated in culture systems in which we interrogated human peripheral blood and hepatic iNKT and MAIT cells. Our findings uncover a previously unappreciated mechanism of stress-induced immunosuppression and implicate the stress response as a potential barrier to iNKT cell- and MAIT cell-based immunotherapies.