Piemonte, Erica (2024) Human TR3-56 cells: exploring a novel immune cell subset in Multiple Sclerosis: connection between EBV infection and disease pathogenesis. [Tesi di dottorato]

	Testo Piemonte_Erica_36_COMPLETO.pdf Visibile a [TBR] Amministratori dell'archivio Download (1MB)
Anteprima	Testo Piemonte_Erica_36_PARZIALE.pdf Download (976kB) | Anteprima

Abstract

Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disorder, resulting from the infiltration of auto-reactive T lymphocytes into the central nervous system (CNS). The immune-pathogenetic mechanisms at the basis of loss of immunological self-tolerance in MS are not completely defined. Recently published evidence from our research group has unveiled a poorly explored T cell subset known as TR3-56 cells, which express CD56 surface molecules. We revealed that TR3-56 cell frequency was reduced in type 1 diabetes (T1D) children and positively associated with β-cell function. Thus, we hypothesized that this T cell subset might be also involved in the occurrence of other autoimmune conditions, such as MS. To this purpose, the research activity in the PhD program was focused on the study of TR3-56 cells in newly diagnosed treatment-naïve Relapsing-Remitting MS (RR-MS) subjects. We found a reduction in the frequency of TR3-56 cells in the blood of newly diagnosed, treatment-naïve RR-MS subjects, and this reduction was inversely correlated with disease severity. Additionally, TR3-56 cells from these subjects exhibited decreased surface expression of activating/inhibitory receptors and cytotoxicity-related molecules compared to healthy controls. Next, TR3-56 cells from RR-MS cohort displayed a significantly decreased expression of CD107a/LAMP-1 and Interferon-γ production, after T cell receptor (TCR) stimulation. Interestingly, TR3-56 cells from RR-MS cohort showed an exhausted phenotype, evident not only from the increased expression levels of typical exhaustion surface markers but also from the reduced intracellular calcium flux following TCR stimulation. Then, we observed a reduced proliferative rate in vitro in TR3-56 cells from RR-MS subjects, along with an impaired TCR signaling cascade. Finally, TR3-56 cells from RR-MS cohort showed a significantly reduced response rate specifically to Epstein-Barr virus (EBV) peptides pool. In conclusion, our results reveal a defect of TR3-56 cell compartment in RR-MS individuals, characterized by an exhausted phenotype, probably due to their role in the elimination of EBV-infected cells. This study reveals an immunological cell population involved in the pathogenesis of MS, potentially representing a novel target for therapeutic interventions in the disease.

Downloads

Actions (login required)

Modifica documento