biostudies-literatureRowntree LCNIAID NIH HHSFederal Government | DHAC | National Health and Medical Research Council (NHMRC)e2503145122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12435269biostudies-literatureUnknown122(36)Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8⁺ T-cells directed against HLA-B*15:01-restricted Spike-derived S_919-927 peptide (B15/S₉₁₉⁺CD8⁺ T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8⁺ T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S₉₁₉⁺CD8⁺ T-cell responses in COVIDProceedings of the National Academy of Sciences of the United States of AmericaHLA-B*15:01-positive severe COVID-19 patients lack CD8<sup>+</sup> T cell pools with highly expanded public clonotypes.PMC12435269U01 AI1446161173871Doherty PCRowntree LCKaewpreedee PPeiris MSonehara KValkenburg SAHabel JRMcKay MRKotsimbos TCGao GFJuno JAKwok JSYCohen CAKent SJPHOSP-COVID Collaborative GroupAllen LFMcQuilten HALeung KSMThwaites RSXu JTurtle LBond KATosif SQuadeer AADavies JLappas MKedzierska KThomas PGTrubiano JAKaity Allen ELewin SRSmibert OCGordon CLEfstathiou CRossjohn JPetersen JHolmes NEChaurasia PNamkoong HPoon LLMWu JTIshii KJLiu WJChan KKPPannaraj PSLittler DRTian JCheng ACCrawford NWThevarajan IHui DSCBrightling CEZhang WLee CKOkada YLee KWKCheng SMSNguyen THOHagen RRWilliamson DAfalseHLA-B*15:01-positive severe COVID-19 patients lack CD8<sup>+</sup> T cell pools with highly expanded public clonotypes.Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8⁺ T-cells directed against HLA-B*15:01-restricted Spike-derived S_919-927 peptide (B15/S₉₁₉⁺CD8⁺ T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8⁺ T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S₉₁₉⁺CD8⁺ T-cell responses in COVID2025-01-01T00:00:00Z2025 Sep2026-06-01T15:50:01.829Z2026-04-08T13:50:39.264ZS-EPMC124352694089291410.1073/pnas.2503145122