Profound suppression of the host MR1-MAIT cell axis by Varicella Zoster Virus

Abstract

Mucosal Associated Invariant T (MAIT) cells are an unconventional immune population that functions to survey mucosal barrier and host entry sites. Through their T cell receptor (TCR), MAIT cells can respond to an evolutionarily conserved pathogen pattern of riboflavin synthesis presented by their cognately antigen presenting molecule: Major histocompatibility complex related gene protein (MR)-1. This allows the MR1-MAIT cell axis to confer resistance against and regulate host-microbiome dynamics. Furthermore, MAIT cells are innately sensitive to TCR-independent activation via local pro-inflammatory cues and thus can play a role in several viral infections. In this thesis we examine the interactions between MR1, MAIT cells and the causative agent of chickenpox (varicella) and shingles (zoster): Varicella zoster virus (VZV). Part of what allows VZV to be a globally prevalent pathogen is its ability to disarm host immune defence responses designed to impair viral replication. Through utilising flow cytometry we reveal that VZV targets immature and surface MR1 expression in MR1 overexpressing epithelial cell lines. Transfection assays identified VZV encoded serine/threonine kinase open reading frame (ORF) 66 as mediator of MR1 downregulation. We also assessed the capacity of VZV to infect primary blood MAIT cells. Flow cytometric analysis revealed that VZV infects MAIT cells at a comparable rate to conventional T cells, whilst also retaining a highly expressed extravasation and skin homing program. Finally, through spectral cytometry and in vitro MAIT cell stimulation assays, we demonstrated a striking abrogation of cytokine production and cytolytic capacity by VZV infected (viral antigen positive) and VZV exposed (viral antigen negative) MAIT cells in response to distinct modalities of activation such as TCR-dependent and cytokine driven activation. Overall the work from this thesis reveals a previously unknown capacity for VZV to disarm the host MR1-MAIT cell axis.