PhD Oral Exam - Mehri Hajiaghayi, Biology

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Background: Stress is a powerful regulator of physiology with broad impacts on immune function. Adaptive immunity is the part of the immune system that detects and responds to new pathogens and cancerous cells. T cells are key regulators of adaptive immunity, coordinating immune responses and maintaining long-lasting immunological memory. T cells express the β₂-adrenergic receptor (β₂-AR), which reacts to ligands including endogenous stress hormones adrenaline and noradrenaline, and a variety of pharmacological compounds. Activation of β₂-AR on T cells with distinct ligands controls cytokine production, differentiation, and effector responses.

To model the effects of stressors on adaptive T cell immunity, I investigated how β₂-AR signaling pathways modulate T cell responses under controlled laboratory conditions using primary human samples stimulated with various β₂-adrenergic ligands. β₂-AR signaling proceeds through two distinct intracellular routes: the canonical Gs–cAMP–PKA pathway and the alternative biased β–arrestin–mediated biased pathway. The project examined “how selective engagement of these pathways, emanating from the same receptor, modulates T cell responses differently.” I first explored this question from a fundamental perspective of cellular signalling in T cells, then I concluded with an application of the knowledge towards immunotherapy of cancer cells. 

Results: In brief, engaging the canonical β₂-AR pathway augmented pro-inflammatory cytokine production in T cells. In contrast, biased β₂-AR signaling suppressed these inflammatory responses. Furthermore, the biased β₂-AR signaling restored cytotoxic function in dysfunctional T cells, which prolonged their anti-cancer potential. 

Relevance: These findings highlight β₂-AR as a modifiable target that enhances or suppresses T cell behavior depending on the signaling route engaged. This work offers insight into how stress-responsive pathways shape immunity and provides a conceptual foundation for developing next-generation immunomodulatory strategies in cancer therapy.