Downregulation of MHC Class I Expression by Influenza A and B Viruses

Marios Koutsakos, Hamish E.G. McWilliam, Turgut E. Aktepe, Svenja Fritzlar, Patricia T. Illing, Nicole A. Mifsud, Anthony W. Purcell, Steve Rockman, Patrick C. Reading, Julian P. Vivian, Jamie Rossjohn, Andrew G. Brooks, Jason M. Mackenzie, Justine D. Mintern, Jose A. Villadangos, Thi H.O. Nguyen, Katherine Kedzierska

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36 Citations (Scopus)


Manipulation of the MHC-I presentation pathway, and thus limiting MHC-I cell surface expression, is used by many viruses to evade immune recognition. In particular, downregulation of MHC-I molecules at the cell surface can reduce the ability of CD8+ T cells to recognize viral peptides presented by MHC-I molecules and thereby delay viral clearance by CD8+ T cells. To date, MHC-I downregulation by influenza viruses has not been reported. Given that influenza virus infections are a global health concern and that CD8+ T cells play an important role in promoting influenza virus clearance and recovery from influenza disease, we investigated whether influenza A and B viruses (IAV, IBV) downregulated MHC-I as a novel mechanism to evade cellular immunity. Here, we showed that infection of several cell types, including epithelial A549 cells, with a panel of IAV and IBV viruses downregulated the surface MHC-I expression on IAV/IBV-infected cells during the late stages of influenza virus infection in vitro. This observation was consistent across a panel of class I-reduced (C1R) cell lines expressing 14 different HLA-A or -B alleles and a panel of 721.221 cell lines expressing 11 HLA-C alleles. Interestingly, IBV infection caused more pronounced reduction in surface MHC-I expression compared to IAV. Importantly, the two viruses utilized two distinct mechanisms for MHC-I downregulation. Our data demonstrated that while IAV caused a global loss of MHC-I within influenza-infected cells, IBV infection resulted in the preferential loss of MHC-I molecules from the cell surface, consequent of delayed MHC-I trafficking to the cell surface, resulting from retaining MHC-I intracellularly during IBV infection. Overall, our study suggests that influenza viruses across both IAV and IBV subtypes have the potential to downregulate MHC-I surface expression levels. Our findings provide new insights into the host-pathogen interaction of influenza A and B viruses and inform the design of novel vaccine strategies against influenza viruses.

Original languageEnglish
Article number1158
Number of pages12
JournalFrontiers in Immunology
Publication statusPublished - 29 May 2019


  • HLA
  • influenza A virus
  • influenza B virus
  • MHC-I
  • T cells

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