Stiftung Tierärztliche Hochschule Hannover (TiHo)

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

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. GND; Rossjohn, Jamie; Gras, Stephanie; Loh, Liyen; Nguyen, Thi H. O.; Kedzierska, Katherine

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.

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Sant, S., Quiñones-Parra, S.M., Koutsakos, M., Grant, E.J., Loudovaris, T., Mannering, S.I., Crowe, J., van de Sandt, C.E., Rimmelzwaan, G.F., Rossjohn, J., Gras, S., Loh, L., Nguyen, T.H.O., Kedzierska, K., 2020. HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells. PLoS pathogens 16. https://doi.org/10.1371/journal.ppat.1008714
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