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 (iNKT) cells. This is not due to iNKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice exhibit a split inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. iNKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, iNKT 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 iNKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression.

Automated summary

Long-term psychological stress inhibits T helper 1 (T(H)1) and T(H)2-type responses by invariant natural killer T (iNKT) cells, without causing cell death. Stress triggers a split inflammatory signature in activated iNKT cells, mediated by glucocorticoid receptor signaling, and impairs their ability to enhance cytotoxicity against lymphoma or reduce metastatic melanoma burden. Stress also affects mucosa-associated invariant T (MAIT) cells' responses, but can be corrected with habituation to predictable stressors.