HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells

Sneha Sant, Sergio M. Quiñones-Parra, Marios Koutsakos, Emma J. Grant, Thomas Loudovaris, Stuart I. Mannering, Jane Crowe, Carolien E. van de Sandt, Guus F. Rimmelzwaan, Jamie Rossjohn, Stephanie Gras, Liyen Loh, Thi H.O. Nguyen, Katherine Kedzierska

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Abstract

Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8+ T-cell responses towards virus-derived peptide/ human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01NP199-207. The immunodominance hierarchies across these universal CD8+ T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8+ T-cell responses directed towards A2/M158 were generally immunodominant, A2/M158+CD8+ T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following ex vivo and in vitro analyses. A2/M158+CD8+ T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M158+CD8+ T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8+ T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8+ T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases.

Original languageEnglish
Article numbere1008714
Number of pages23
JournalPLoS Pathogens
Volume16
Issue number8
DOIs
Publication statusPublished - 4 Aug 2020

Keywords

  • T cells
  • cytotoxic T cells
  • immune response
  • spleen
  • influenza A virus
  • viral vaccines
  • influenza
  • influenza viruses

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