PhD Oral Exam - Fatemeh Gholizadehhosseinabadi, 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: Acetylcholine (ACh), traditionally recognized as a key neurotransmitter of the parasympathetic nervous system, can modulate immune function. Immune cells produce ACh and respond to it through muscarinic and nicotinic receptors, forming a non-neuronal cholinergic network. How this system shapes human memory T helper (Th) cell responses remains unclear. Memory Th cells persist long after antigen exposure and drive rapid secondary immune responses by coordinating cytokine production and supporting B-cell function. Dysregulated memory Th-cell responses are implicated in immune-mediated disease, in part through altered cytokine production and impaired control of antibody responses. Notably, memory Th cells are an important source of ACh, suggesting they may regulate their own activity. These cells include central memory and effector memory subsets, which differ in their function and responsiveness. This thesis investigates how ACh receptor signaling, particularly through M3 muscarinic receptors (M3R) and α7 nicotinic acetylcholine receptors (α7 nAChR), regulates memory Th cell function and humoral immune responses.

Results: ACh receptor signaling had receptor-specific and functionally opposing effects in memory Th cells. M3R activation promoted inflammatory responses by increasing pro-inflammatory cytokine production. In contrast, α7 nAChR activation suppressed activation-associated and helper functions, with stronger effects in central memory Th cells. This inhibitory signaling reduced cytokine production, downregulated genes that control helper T-cell identity, and impaired the ability of memory Th cells to support B-cell responses, leading to reduced generation of antibody-producing cells and lower antibody production.

Relevance: These findings identify a “cholinergic checkpoint” in human memory Th cells, in which M3R signaling enhances inflammatory responses, whereas α7 nAChR signaling restrains activation and helper function, particularly in central memory subsets. This receptor-specific balance represents an additional layer of immune regulation that controls memory Th-cell activity and T cell–dependent B-cell responses. By defining how ACh receptor signaling shapes memory T-cell and T cell–dependent B-cell responses under baseline conditions, this work provides a framework for studying cholinergic regulation in disease settings and highlights cholinergic receptor pathways as potential targets for modulating pathological immune responses.