PMID- 32750095 OWN - NLM STAT- MEDLINE DCOM- 20201007 LR - 20201007 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 16 IP - 8 DP - 2020 Aug TI - HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells. PG - e1008714 LID - 10.1371/journal.ppat.1008714 [doi] LID - e1008714 AB - 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 TCRalphabeta 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 TCRalphabeta 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. FAU - Sant, Sneha AU - Sant S AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Quinones-Parra, Sergio M AU - Quinones-Parra SM AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Koutsakos, Marios AU - Koutsakos M AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Grant, Emma J AU - Grant EJ AUID- ORCID: 0000-0001-7193-9427 AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Loudovaris, Thomas AU - Loudovaris T AUID- ORCID: 0000-0002-7038-2302 AD - Immunology and Diabetes Unit, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. FAU - Mannering, Stuart I AU - Mannering SI AUID- ORCID: 0000-0003-3497-3559 AD - Immunology and Diabetes Unit, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. FAU - Crowe, Jane AU - Crowe J AD - Deepdene Surgery, Deepdene, Victoria, Australia. FAU - van de Sandt, Carolien E AU - van de Sandt CE AUID- ORCID: 0000-0002-4155-7433 AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. AD - Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands. FAU - Rimmelzwaan, Guus F AU - Rimmelzwaan GF AD - National Influenza Center and Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom. FAU - Gras, Stephanie AU - Gras S AUID- ORCID: 0000-0001-7416-038X AD - Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. FAU - Loh, Liyen AU - Loh L AUID- ORCID: 0000-0002-1676-0579 AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Nguyen, Thi H O AU - Nguyen THO AUID- ORCID: 0000-0002-9294-7693 AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. FAU - Kedzierska, Katherine AU - Kedzierska K AUID- ORCID: 0000-0001-6141-335X AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200804 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-B*27:05 antigen) RN - 0 (HLA-B27 Antigen) RN - 0 (Immunodominant Epitopes) SB - IM MH - Adult MH - Aged MH - CD8-Positive T-Lymphocytes/*immunology MH - Epitopes, T-Lymphocyte/immunology MH - Female MH - HLA-B27 Antigen/*genetics/immunology MH - Humans MH - Immunodominant Epitopes/genetics/*immunology MH - Immunologic Memory MH - Influenza A virus/physiology MH - Influenza, Human/genetics/*immunology/virology MH - Male MH - Middle Aged MH - Young Adult PMC - PMC7428290 COIS- The authors have declared that no competing interests exist. EDAT- 2020/08/05 06:00 MHDA- 2020/10/08 06:00 PMCR- 2020/08/04 CRDT- 2020/08/05 06:00 PHST- 2020/04/09 00:00 [received] PHST- 2020/06/18 00:00 [accepted] PHST- 2020/08/14 00:00 [revised] PHST- 2020/08/05 06:00 [pubmed] PHST- 2020/10/08 06:00 [medline] PHST- 2020/08/05 06:00 [entrez] PHST- 2020/08/04 00:00 [pmc-release] AID - PPATHOGENS-D-20-00714 [pii] AID - 10.1371/journal.ppat.1008714 [doi] PST - epublish SO - PLoS Pathog. 2020 Aug 4;16(8):e1008714. doi: 10.1371/journal.ppat.1008714. eCollection 2020 Aug.