Chronic stress physically spares but functionally impairs innate-like invariant T cells
Patrick T. Rudak,
Joshua Choi,
Katie M. Parkins,
Kelly L. Summers,
Dwayne N. Jackson,
Paula J. Foster,
Anton I. Skaro,
Ken Leslie,
Vivian C. McAlister,
Vijay K. Kuchroo,
Wataru Inoue,
Olivier Lantz,
S.M. Mansour Haeryfar
Affiliations
Patrick T. Rudak
Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada
Joshua Choi
Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada
Katie M. Parkins
Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada; Robarts Research Institute, Western University, London, ON N6A 5B7, Canada
Kelly L. Summers
Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada
Dwayne N. Jackson
Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada
Paula J. Foster
Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada; Robarts Research Institute, Western University, London, ON N6A 5B7, Canada
Anton I. Skaro
Department of Surgery, Division of General Surgery, Western University, London, ON N6A 4V2, Canada
Ken Leslie
Department of Surgery, Division of General Surgery, Western University, London, ON N6A 4V2, Canada
Vivian C. McAlister
Department of Surgery, Division of General Surgery, Western University, London, ON N6A 4V2, Canada
Vijay K. Kuchroo
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115, USA
Wataru Inoue
Robarts Research Institute, Western University, London, ON N6A 5B7, Canada; Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada
Olivier Lantz
Laboratoire d’Immunologie and INSERM U932, PSL University, Institut Curie, 75248 Paris Cedex 5, France
S.M. Mansour Haeryfar
Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada; Department of Surgery, Division of General Surgery, Western University, London, ON N6A 4V2, Canada; Department of Medicine, Division of Clinical Immunology and Allergy, Western University, London, ON N6A 5A5, Canada; Corresponding author
Summary: 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 (TH1)- and TH2-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 TH1-/TH2-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.
