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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Haeryfar, Mansour

Abstract

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.

Summary for Lay Audience

The nervous system is critical for regulating the immune system. During psychological stress, normal interactions between the nervous system and the immune system can become disrupted, leading to a reduced ability of the immune system to respond to microbial infections and tumors. However, we still have a poor understanding of why there exists a relationship between stress, weakened immune responses, and greater susceptibility to infectious diseases and cancer. For example, how stress affects particular subsets of immune cells known as invariant natural killer T (iNKT) cells and mucosa-associated invariant T (MAIT) cells, which react rapidly to microbes and tumors and alert other immune cell types of impending danger, is essentially unknown. In this thesis, I investigated how stress impacts the function of iNKT and MAIT cells using multiple methods with which to induce psychological stress in mice. I demonstrate that pro-inflammatory cytokine production by activated iNKT cells is diminished in stressful environments, but only when mice are incapable of predicting the stressor being applied. Instead, iNKT cells from stressed mice trigger an abnormal immune response typified by anti-inflammatory cytokine production. Next, I found that these atypical responses are a consequence of glucocorticoids, a major stress hormone, acting directly on iNKT cells. Moreover, these glucocorticoids cause iNKT cells to increase their expression of the inhibitory molecule T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), which limits their responsiveness, and blocking this pathway partially restores their functional capacity during stress. Ultimately, iNKT cells in stressed mice fail to protect against cancer including lung metastases derived from melanoma. Consistent with the above results, MAIT cells in stressed mice also upregulate TIGIT and have a diminished ability to produce pro-inflammatory cytokines. Since mediators of stress are capable of killing immune cells, it was important to discern whether these effects on invariant T cell function were due to their death. To the contrary, I discovered that iNKT and MAIT cells are unusually resistant to stress-induced cell death. Collectively, these findings reveal previously unidentified modes of stress-induced immunosuppression and implicate the stress response as a hurdle for harnessing iNKT and MAIT cells to prevent disease.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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