@article{022b4ef7c5c74328a9cd4d90b671babe,
title = "CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity",
abstract = "To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.",
keywords = "COVID-19, immunodominant, SARS-CoV-2-specific CD8+, T cells, TCR",
author = "Nguyen, {Thi H.O.} and Rowntree, {Louise C.} and Jan Petersen and Chua, {Brendon Y.} and Luca Hensen and Lukasz Kedzierski and {van de Sandt}, {Carolien E.} and Priyanka Chaurasia and Tan, {Hyon Xhi} and Habel, {Jennifer R.} and Wuji Zhang and Allen, {Lilith F.} and Linda Earnest and Mak, {Kai Yan} and Juno, {Jennifer A.} and Kathleen Wragg and Mordant, {Francesca L.} and Fatima Amanat and Florian Krammer and Mifsud, {Nicole A.} and Doolan, {Denise L.} and Flanagan, {Katie L.} and Sabrina Sonda and Jasveen Kaur and Wakim, {Linda M.} and Westall, {Glen P.} and Fiona James and Effie Mouhtouris and Gordon, {Claire L.} and Holmes, {Natasha E.} and Smibert, {Olivia C.} and Trubiano, {Jason A.} and Cheng, {Allen C.} and Peter Harcourt and Patrick Clifton and Crawford, {Jeremy Chase} and Thomas, {Paul G.} and Wheatley, {Adam K.} and Kent, {Stephen J.} and Jamie Rossjohn and Joseph Torresi and Katherine Kedzierska",
note = "Funding Information: We thank all the participants involved in the study, as well as Robyn Esterbauer, Hannah Kelly, Jane Batten, Helen Kent, and Kanta Subbarao for support with the cohorts and assays. We thank Jill Garlick, Janine Roney, Anne Paterson, and the research nurses at the Alfred Hospital. We acknowledge all DRASTIC (The use of cytokines as a preDictoR of disease Severity in criTically Ill Covid-patients) investigators from Austin Health and thank the participants involved. We thank Ana Copaescu for laboratory work and study coordination for the DRASTIC study. We thank Thomas Loudovaris and Stuart I. Mannering from St Vincent{\textquoteright}s Institute of Medical Research for access to spleen samples. This work was supported by the Clifford Craig Foundation to K.L.F. and K.K.; an NHMRC Leadership Investigator Grant to K.K. ( 1173871 ); an NHMRC Emerging Leadership Level 1 Investigator Grant to THON ( 1194036 ); an NHMRC program grant to D.L.D. ( 1132975 ); the Research Grants Council of the Hong Kong Special Administrative Region, China ( T11-712/19-N ) to K.K.; the Victorian government to S.J.K. and A.K.W.; an MRFF award ( 2002073 ) to S.J.K. and A.K.W.; an MRFF award ( 1202445 ) to K.K.; an MRFF award ( 2005544 ) to K.K., S.J.K., J.A.J., and A.K.W.; an NHMRC program grant ( 1149990 ) to S.J.K.; an NHMRC project grant ( 1162760 ) to A.K.W.; and NIH contract CIVR-HRP ( HHS-NIH-NIAID-BAA2018 ) to P.G.T. and K.K. A.K.W. is supported by an Emerging Leadership 1 Investigator Grant ( 1173433 ), J.A.J. by an NHMRC Early Career Fellowship (ECF) ( 1123673 ), D.L.D. by an NHMRC Principal Research Fellowship ( 1137285 ), and S.J.K. by an NHMRC Senior Principal Research Fellowship ( 1136322 ). C.E.S. has received funding from the European Union {\textquoteright}s Horizon 2020 research, innovation program under the Marie Sk{\l}odowska-Curie grant agreement ( 792532 ) and the Doherty Collaborative Seed Grant. J.R. is supported by an ARC Laureate fellowship. J.R.H. and W.Z. are supported by the Melbourne Research Scholarship from the University of Melbourne. L.H. is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne. J.C.C. and P.G.T. are supported by NIH NIAID ( R01 AI136514-03 ) and ALSAC at St. Jude. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = may,
day = "11",
doi = "10.1016/j.immuni.2021.04.009",
language = "English",
volume = "54",
pages = "1066--1082.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "5",
}
