Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection

Martina Milighetti; Yanchun Peng; Cedric Tan; Michal Mark; Gayathri Nageswaran; Suzanne Byrne; Tahel Ronel; Tom Peacock; Andreas Mayer; Aneesh Chandran; Joshua Rosenheim; Matthew Whelan; Xuan Yao; Guihai Liu; Suet Ling Felce; Tao Dong; Alexander J Mentzer; Julian C Knight; Francois Balloux; Erez Greenstein; Shlomit Reich-Zeliger; Corinna Pade; Joseph M Gibbons; Amanda Semper; Tim Brooks; Ashley Otter; Daniel M Altmann; Rosemary J Boyton; Mala K Maini; Aine McKnight; Charlotte Manisty; Thomas A Treibel; James C Moon; COVIDsortium Investigators; Mahdad Noursadeghi; Benny Chain

doi:10.1016/j.isci.2023.106937

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection

iScience. 2023 Jun 16;26(6):106937. doi: 10.1016/j.isci.2023.106937. Epub 2023 May 22.

Authors

Martina Milighetti¹, Yanchun Peng^{2

3}, Cedric Tan⁴, Michal Mark⁵, Gayathri Nageswaran¹, Suzanne Byrne¹, Tahel Ronel¹, Tom Peacock¹, Andreas Mayer¹, Aneesh Chandran¹, Joshua Rosenheim¹, Matthew Whelan¹, Xuan Yao³, Guihai Liu³, Suet Ling Felce³, Tao Dong^{2

3}, Alexander J Mentzer⁶, Julian C Knight^{3

6}, Francois Balloux⁴, Erez Greenstein⁵, Shlomit Reich-Zeliger⁵, Corinna Pade⁷, Joseph M Gibbons⁷, Amanda Semper⁸, Tim Brooks⁸, Ashley Otter⁸, Daniel M Altmann⁹, Rosemary J Boyton^{10

11}, Mala K Maini¹, Aine McKnight⁷, Charlotte Manisty¹², Thomas A Treibel¹², James C Moon¹²; COVIDsortium Investigators; Mahdad Noursadeghi¹, Benny Chain¹

Affiliations

¹ Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
² MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
⁴ UCL Genetics Institute, University College London, London WC1E 6BT, UK.
⁵ Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
⁶ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷ Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.
⁸ UK Health Security Agency, Porton Down, Salisbury SP4 0JG, UK.
⁹ Department of Immunology and Inflammation, Imperial College London, London SW7 2BX, UK.
¹⁰ Department of Infectious Disease, Imperial College London, London W12 0NN, UK.
¹¹ Lung Division, Royal Brompton Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹² Institute of Cardiovascular Sciences, University College London, London WC1E 6BT, UK.

Abstract

T cell responses precede antibody and may provide early control of infection. We analyzed the clonal basis of this rapid response following SARS-COV-2 infection. We applied T cell receptor (TCR) sequencing to define the trajectories of individual T cell clones immediately. In SARS-COV-2 PCR+ individuals, a wave of TCRs strongly but transiently expand, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains but not with circulating human coronaviruses. Many expanding CDR3s were present at high frequency in pre-pandemic repertoires. Early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the preinfection naive repertoire. High-frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.

Keywords: Biological sciences; Cell biology; Immunity; Immunology.