Poster Presentation CD1-MR1 2024

Infection and functional impairment of MAIT cells by herpes simplex virus type 1 (#223)

Zoe Emanuel 1 2 3 , Katherine Willis 1 2 3 , Lauren Stern 1 2 3 , Renee Traves 1 2 3 , Shivam K Purohit 1 2 , Carolyn Samer 1 2 , Alexandra J Corbett 4 , Allison Abendroth 1 2 5 , Barry Slobedman 1 2 5
  1. Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  2. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  3. Contributed equally,
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  5. These authors contributed equally,

Herpes simplex virus type 1 (HSV-1) is a highly prevalent human herpesvirus which infects approximately two-thirds of individuals worldwide, typically causing vesicular lesions (‘cold sores’) at the orolabial mucosa. The success and lifelong persistence of HSV-1 is partly attributed to the range of immunoevasive mechanisms employed by the virus, which include viral downregulation of classical and non-classical antigen presentation molecules, such as MHC-I, CD1d and MR1. Although HSV-1 infects and replicates at mucocutaneous regions, interactions between the virus and mucosal-associated invariant T (MAIT) cells are largely uncharacterised. Here we report for the first time that HSV-1 is capable of directly infecting peripheral blood MAIT cells and manipulating their effector phenotype. Using spectral cytometry and tetramer-based identification of MAIT cells, we show using an in vitro model of infection that HSV-1 infects distinct primary human MAIT cell subsets (CD4+, CD8+, CD4-CD8-, and CD4+CD8+) and alters their activation profile in response to stimulation via T-cell receptor (TCR)-dependent and TCR-independent pathways. The impact of HSV-1 infection on MAIT cell function is profound and involves the suppression of cell-surface activation markers (CD25, CD69, PD-1), impaired expression of key cytokine receptors IL-18R and IL-12R, and potent inhibition of Th1-associated cytokine production (IFN-γ, TNF). Further, HSV-1 infected MAIT cells display reduced cytotoxic potential, with limited degranulation and perforin/granzyme B expression following stimulation with the MR1 ligand 5-OP-RU and/or cytokines. Across a range of effector outputs, we also find that HSV-1 impacts the functional capacity of ‘bystander’ MAIT cells, which are exposed to HSV-1 infection but remain viral antigen-negative. Collectively, this work reveals MAIT cells are susceptible to functional disruption via infection or exposure to a prevalent human herpesvirus. This adds to our growing understanding of the effects of viral infection on MAIT cell phenotype and function.