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

Schultz-Cherry, Stacey, Sant, Sneha, Quiñones-Parra, Sergio M., Koutsakos, Marios, Grant, Emma J., Loudovaris, Thomas, Mannering, Stuart I., Crowe, Jane, van de Sandt, Carolien E., Rimmelzwaan, Guus F., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Gras, Stephanie, Loh, Liyen, Nguyen, Thi H. O. and Kedzierska, Katherine 2020. HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells. PLoS Pathogens 16 (8) , e1008714. 10.1371/journal.ppat.1008714

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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*57:01-NP199-207. 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Public Library of Science
ISSN:	1553-7366
Date of First Compliant Deposit:	20 August 2020
Date of Acceptance:	18 June 2020
Last Modified:	03 May 2023 16:06
URI:	https://orca.cardiff.ac.uk/id/eprint/134291

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