The Role of Acetylcholine Producing T cells in Hypertensive Heart Disease and Viral Myocarditis
Year: 2026
Type: dissertation
Abstract: The need for an immune response to clear pathogens is balanced by the risks of bystander injury, yet the mechanisms regulating these critical trade-offs remain unclear. Here, ChAT+ T cells were found to be associated with many of these trade-offs. Choline acetyltransferase-expressing (ChAT+) T cells have been linked to neuro-immune control of vascular flow and leukocyte recruitment, so we asked how T-cell acetylcholine (ACh) production regulates immune mediated outcomes to non-ischemic cardiomyopathy, particularly hypertensive (sterile) and viral (infectious) cardiac injury, focusing on the myocardium, an organ with little regenerative ability.Encephalomyocarditis virus (EMCV) infection primed differentiated and cytotoxic CD4+ T cells to express high levels of ChAT, indicating that ChAT upregulation was activation-linked. Hypertensive stress weakly activated T cell ChAT expression at a fraction of the viral model. Use of mice with a T cell-specific ChAT deletion (T-ChATKO; ChATfl/flCD4cre) demonstrated a strong age associated bias in disease outcomes. Middle-aged hypertensive and male adolescent viral infections resulted in increased mortality in the absence of T cell specific ACh production. In the EMCV model, infection resulted in male specific increased infiltration of T cell and monocyte influx, without a change to cardiac injury. In adolescents, there was evidence of viral disseminationand multi-organ pathology, including hind limb paralysis, encephalomyelitis and diaphragmitis. Paradoxically, susceptible male T-ChATKO mice had reduced levels of astrocyte stress, decreased CCR2+ myeloid cell influx to the brain, and serum cytokines that activated monocytes (CCL2, GM-CSF). Within the dural meninges T-ChATKO males had increased myeloid cell influx, indicating that T-cell ChAT expression controlled immune recruitment through compartment-dependent effects. By increasing viral pathogenicity (with age), there was increased organ injury to maintain survival, suggesting a calculated trade-off of neuroinflammatory complications and survival. This work unveils a novel neuro-immune axis that is critical for survival in adolescent viral infection.
Source: TSpace (University of Toronto)
Author: Lin, Julia Mei-Ting
Institution: University of Toronto
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204017712