The impacts of psychological stress on innate-like invariant T cell survival, phenotype, and function
The nervous system serves numerous critical roles in the regulation of immune responses. Consequently, psychological stress can result in immunosuppressive states that are conducive to the development of infection and cancer. Yet, whether stress impacts the functions of innate-like T lymphocytes including invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, which participate in early host defense against pathogens and tumors, remains poorly understood. In this thesis, I leveraged multiple established methods with which to induce psychological stress in mice. I demonstrate that TH1- and TH2-type immune responses initiated by iNKT cells are abrogated during stress, effects which are lost upon habituation to homotypic stressors. Instead, iNKT cells in stressed mice trigger an abnormal systemic inflammatory response characterized by striking levels of interleukin (IL)-10, IL-23, and IL-27. These dysregulated responses are driven by iNKT cell-intrinsic glucocorticoid receptor (GR) signaling. Accordingly, iNKT cells upregulate the co-inhibitory molecule T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) in a GR-dependent manner and blockade of TIGIT partially restores their functional capacity in stressed mice. Ultimately, in a GR-dependent fashion, iNKT cells from stressed mice fail to prevent pulmonary metastases of B16 melanoma. MAIT cells also upregulate TIGIT and are incapable of mounting optimal TH1- and TH2-type responses during stress. Lastly, these inhibitory effects are not simply due to cell death since human and mouse iNKT and MAIT cells are unusually refractory to glucocorticoid-induced apoptosis. Collectively, my findings reveal a mechanism of stress-induced immunosuppression with implications for iNKT or MAIT cell-based immunotherapies.
psychological stress, sympathetic nervous system, hypothalamic-pituitary-adrenal axis, glucocorticoids, invariant natural killer T cells, mucosa-associated invariant T cells, apoptosis, TIGIT, cytokines, immunosuppression
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