The first identification of immunodominant CD8<sup>+</sup> T cell cross-reactivity across influenza types A, B and C — ASN Events
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The first identification of immunodominant CD8+ T cell cross-reactivity across influenza types A, B and C (#89)

Marios Koutsakos 1 , Patricia Illing 2 , Oanh Nguyen 1 , Nicole Mifsud 2 , Bridie Clemens 1 , Sneha Sant 1 , Chinn Yi Wong 1 , Emma Allen 3 , Don Teng 4 , Auda Eltahla 5 , Simone Rizzetto 5 , Steve Rockman 1 6 , David Jackson 1 , Jamie Rossjohn 2 , Dhanasekaran Vijaykrishna 4 , Linda Wakim 1 , Fabio Lucianni 5 , Paul Thomas 3 , Stephanie Gras 2 , Anthony Purcell 2 , Katherine Kedzierska 1
  1. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  2. Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  3. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA
  4. Infection and Immunity Program & Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  5. School of Medical Sciences and The Kirby Institute, UNSW, Sydney, NSW, Australia
  6. Seqirus, Parkville, VIC, Australia

Cytotoxic CD8+ T cells confer heterosubtypic protection against influenza A viruses (IAV). In contrast, little or nothing is known about CD8+ T cell responses to co-circulating influenza B viruses (IBV) or C viruses (ICV), which also cause substantial human infection. We therefore characterized CD8+ T cell responses to IBV/ICV and assessed the breadth of cross-recognition across the three influenza types. Genetic analysis identified several peptides highly conserved across IAV and IBV, including PB1413-421, which was also conserved in ICV and was presented by the widely-expressed HLA-A*02:01 molecule. Importantly, A2/PB1413-421-specific CD8+ T cells could be recalled by all three influenza types in vitro. These universally cross-reactive CD8+ T cells were of high peptide-MHC-I and functional avidity, and responded with a polyfunctional cytokine profile. Furthermore, immunopeptidome analysis of IBV-infected cells identified 66 novel peptides naturally presented by HLA-A*02:01. Of these, three were immunogenic in HLA-A2-expressing mice, exhibiting distinct immunodominance hierarchies. Memory CD8+ T cells against these novel IBV-specific epitopes were readily detected in healthy adults, and targeted towards two HA- and NS1-derived peptides, contrasting the known immunodominance of responses to M1/NP-derived epitopes from IAV. Analysis of CD8+ T cell responses in PBMCs from influenza-infected individuals and healthy human lungs revealed that the universally cross-reactive population was immunodominant over the IBV-specific populations. Single-cell RNAseq, TCR repertoire analyses and structural analysis of the competing CD8+ T cell populations allowed us to delineate the molecular mechanism underpinning this immunodominance hierarchy. Our work introduces a new paradigm, whereby immunodominant CD8+ T cells can confer unprecedented cross-reactivity across IAV, IBV and ICV, which is broader than any known T cell or antibody population against influenza viruses. Epitopes of such cross-reactive CD8+ T cells will be key to the design of universal influenza vaccines that do not require annual reformulation.

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