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

Area of Science:

• Immunology
• Neuroimmunology
• Cellular Biology

Background:

• Psychological stress negatively impacts T lymphocytes.
• The effect of stress on innate-like T cells, such as iNKT and MAIT cells, remains largely unknown.
• Understanding stress-induced immune modulation is crucial for public health.

Purpose of the Study:

• To investigate the impact of long-term psychological stress on invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cell functions.
• To elucidate the mechanisms underlying stress-induced alterations in these innate-like T cells.
• To assess the consequences of stress on iNKT/MAIT cell-mediated immune responses, including anti-cancer immunity.

Main Methods:

• Long-term stress models in mice.
• Flow cytometry and cytokine analysis to assess iNKT and MAIT cell responses.
• Apoptosis assays to evaluate cell survival under stress.
• Glucocorticoid receptor signaling pathway analysis.
• In vivo studies of anti-lymphoma and anti-melanoma activity.
• Human peripheral blood and hepatic iNKT/MAIT cell cultures.

Main Results:

• Long-term stress abrogates T helper 1 (T_H1) and T_H2 responses orchestrated by iNKT cells, without causing cell death.
• Activated iNKT cells in stressed mice show a "split" inflammatory signature with increased IL-10, IL-23, and IL-27.
• Stress-induced iNKT cell dysfunction is mediated by cell-autonomous glucocorticoid receptor signaling.
• Stress impairs iNKT cell-mediated cytotoxicity against lymphoma and reduces melanoma burden.
• Stress spares MAIT cells physically but hinders their T_H1/T_H2 responses.
• Findings were corroborated in human iNKT/MAIT cell cultures.

Conclusions:

• Psychological stress induces immunosuppression by dysregulating iNKT and MAIT cell functions.
• Glucocorticoid receptor signaling is a key mediator of stress-induced immune impairment in these cells.
• Habituation to predictable stressors can correct iNKT cell dysregulation.
• Stress significantly compromises iNKT/MAIT cell-driven anti-cancer immunity.
• These findings highlight a novel mechanism of stress-induced immune suppression relevant to both mouse models and humans.