Poster Presentation Lorne Infection and Immunity 2022

Novel immunomodulation of the non-classical major histocompatibility complex class I-related (MR1) protein and mucosal associated invariant T (MAIT) cells by human herpesviruses (#209)

Barry Slobedman 1 , Carolyn Samer 1 , Lauren Stern 1 , Shivam Purohit 1 , Caroline Ashley 1 , Hamish McWilliam 2 3 , Brian McSharry 1 , Helen McGuire 1 4 , Emily Blyth 5 6 7 , Allison Abendroth 1
  1. Infection, Immunity and Inflammation. School of Medical Sciences. Charles Perkins Centre, Faculty of Medicine and Health. University of Sydney, Sydney
  2. Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute of Infection and Immunity, Melbourne
  3. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne
  4. Ramaciotti Facility for Human Systems Biology, University of Sydney, Camperdown, NSW, Australia
  5. Blood and Marrow Transplant Unit, Westmead Hospital, Westmead, NSW, Australia
  6. Faculty of Medicine and Health, University of Sydney, Sydney
  7. Westmead Institute for Medical Research, Westmead, NSW, Australia

The antigen-presenting molecule MR1 presents microbial metabolite ligands from vitamin B2 biosynthesis to Mucosal Associated Invariant T cells (MAIT cells). While bacteria and fungi drive the MR1 biosynthesis pathway, viruses do not synthesise vitamin B metabolites and thus had not previously been implicated in MR1 expression or its antigen presentation. We have taken a multi-faceted approach to explore the relationship between herpesvirus infections and MR1 and/or MAIT cell responses.

We demonstrate that several human herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1), varicella zoster virus (VZV) and human cytomegalovirus (HCMV). However, these viruses appear to employ distinct mechanisms to modulate MR1. For example, whilst HSV-1 and VZV profoundly impair total MR1 protein expression, MR1 that had already trafficked to the cell surface before infection was protected from virus-mediated targeting, yet HCMV efficiently targeted both intracellular and pre-existing surface MR1. We also show that a consequence of MR1 targeting is an impaired capacity of the MAIT TCR and/or primary MAIT cells to recognise MR1-restricted ligands during infection of target cells. Thus, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT cell axis.

In our related studies profiling immune reconstitution in haematopoietic stem cell transplant (HSCT) patients with the complication of HCMV reactivated infection, we identify MAIT cell levels at the initial detection of HCMV reactivation as distinguishing patients who subsequently developed low-level versus high-level HCMV reactivation. This data in the HSCT setting highlights MAIT cell levels at the first detection of reactivation as a prognostic marker that may guide clinical decisions regarding pre-emptive therapy. In summary, we provide the first identification of virus-mediated modulation of the MR1 antigen presentation pathway as well as identify impacts on MAIT cells in a clinically relevant setting of virus infection.