Chronic stress physically spares but functionally impairs innate-like invariant T cells

The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress surprisingly abrogates both T helper 1 (T H 1)- and T H 2-type responses orchestrated by invariant natural killer T ( i NKT) cells. This is not due to i NKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated i NKT cells in stressed mice exhibit a "split" inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. i NKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, i NKT cells fail to potentiate cytotoxicity against lymphoma or to reduce the burden of metastatic melanoma. Finally, stress physically spares mouse mucosa-associated invariant T (MAIT) cells but hinders their T H 1-/T H 2-type responses. The above findings are corroborated in human peripheral blood and hepatic i NKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression.