Mapping protective influenza-specific CD8<sup>+</sup> T cell targets for HLA-A*24:02 in Indigenous populations — ASN Events
  1. Schedule
  2. Workshop 7: Infection and Immunity 2
  3. Mapping protective influenza-specific CD8+ T cell targets for HLA-A*24:02 in Indigenous populations

Mapping protective influenza-specific CD8+ T cell targets for HLA-A*24:02 in Indigenous populations (#73)

Bridie Clemens 1 , Patricia Illing 2 , Nicole Mifsud 2 , Luca Hensen 1 , Marios Koutsakos 1 , Emma Grant 3 , Zhongfang Wang 1 , Weiguang Zeng 1 , Stephanie Gras 2 4 , Adrian Miller 5 , Jamie Rossjohn 2 3 4 , Steven Tong 6 7 , David Jackson 1 , Anthony Purcell 2 , Katherine Kedzierska 1
  1. Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  2. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  3. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales
  4. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
  5. Office of the Pro Vice-Chancellor Indigenous Leadership, Charles Darwin University, Darwin, Northern Territory, Australia
  6. Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  7. Menzies School of Health Research, Casuarina, Northern Territory, Australia

Indigenous populations, including Indigenous Australians, experience a higher burden of influenza disease compared to non-Indigenous populations and the underlying mechanisms are unknown. Our previous work suggests that failure of the predominant HLA allomorphs maintained within Indigenous populations to generate a diverse antiviral T-cell response may predispose them to more severe influenza disease. As carriage of HLA-A*24:02 is linked to influenza-induced mortality and this allele is highly expressed in Indigenous populations worldwide, including Indigenous Australians (~25%) and Alaskans (~70%), we evaluated the protective immunogenic influenza CD8+ T-cell targets in A*24:02-expressing mice and humans. To understand the breadth of influenza peptide targets capable of being presented by the A*24:02 molecule, we performed immunopeptidome studies using an infected HLA-A*24:02-expressing cell line and identified natural presentation of 38 peptides derived from 6/11 influenza virus proteins. Strikingly, these peptides were mainly derived from the PB2 (15/38 peptides) and PB1 (10/38 peptides) viral antigens, contrasting with the preference of other prominent HLA alleles to bind NP and M1 peptides. We screened A*24:02-presented peptides as well as 6 previously predicted A*24:02-binding influenza peptides in transgenic HLA-A24-expressing mice. Eight peptides were immunogenic with five inducing immunodominant CD8+ T-cell responses at day 10 after infection. Upon secondary challenge, responses to two of these peptides derived from PB1 and PB2 emerged as immunodominant. In A*24:02+ Indigenous and non-Indigenous donors, modest memory CD8+ T-cell populations focused on these highly conserved PB1 and PB2 peptides. As PB1 and PB2 are omitted from T-cell vaccines in current clinical trials, we used lipopeptide vaccines to probe the protective efficacy of these immunogenic peptides in HLA-A24-expressing mice and assessed their potential as candidate vaccine targets. Our findings demonstrate that the success of a protective broad-spectrum influenza T-cell vaccine for Indigenous people depends on understanding the distinct, HLA-determined, immunogenic T-cell targets specific to these vulnerable populations.

#ASI2017QLD