TY - JOUR
T1 - Global patterns of antigen receptor repertoire disruption across adaptive immune compartments in COVID-19
AU - Joseph, Magdalene
AU - Wu, Yin
AU - Dannebaum, Richard
AU - Rubelt, Florian
AU - Zlatareva, Iva
AU - Lorenc, Anna
AU - Du, Zhipei Gracie
AU - Davies, Daniel
AU - Kyle-Cezar, Fernanda
AU - Das, Abhishek
AU - Gee, Sarah
AU - Seow, Jeffrey
AU - Graham, Carl
AU - Telman, Dilduz
AU - Bermejo, Clara
AU - Lin, Hai
AU - Asgharian, Hosseinali
AU - Laing, Adam G.
AU - Del Molino Del Barrio, Irene
AU - Monin, Leticia
AU - Muñoz-Ruiz, Miguel
AU - McKenzie, Duncan R.
AU - Hayday, Thomas S.
AU - Francos-Quijorna, Isaac
AU - Kamdar, Shraddha
AU - Davis, Richard
AU - Sofra, Vasiliki
AU - Cano, Florencia
AU - Theodoridis, Efstathios
AU - Martinez, Lauren
AU - Merrick, Blair
AU - Bisnauthsing, Karen
AU - Brooks, Kate
AU - Edgeworth, Jonathan
AU - Cason, John
AU - Mant, Christine
AU - Doores, Katie J.
AU - Vantourout, Pierre
AU - Luong, Khai
AU - Berka, Jan
AU - Hayday, Adrian C.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank all patients and blood donors who participated in this study, as well as the medical and research teams at Guy’s and St. Thomas’ Hospitals. Schema figures were created with BioRender.com. We likewise thank our colleagues for discussions and for their support. This study was supported by a Cancer Research Institute Irvington Fellowship (D.R.M.); Cancer Research UK (CRUK) Cancer ImmunoTherapy Accelerator (A.C.H., I.D.M.D.B.); CRUK City of London Major Cancer Centre studentship C604/A27440 (M.J.); European Molecular Biology Organization Long-term Fellowship 198-2018 (M.M.R.); Francis Crick Institute, which receives core funding from CRUK (grant FC001093), Medical Research Council (MRC) grant FC001093, and the Wellcome Trust (grant FC001093; A.C.H., L. Monin, and F.C.); John Black Charitable Foundation (A.C.H.); King’s Together Rapid COVID-19 Call Award (K.J.D.); King’s Together Seed Fund (A.C.H.); MRC King’s College London Doctoral Training Partnership in Biomedical Sciences grant MR/N013700/1 (C.G., S.G.); National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship (A.D. and Y.W.); NIHR Biomedical Research Centre for the Infectious Diseases Biobank (J.C. and C.M.); Rosetrees Trust (A.C.H.); Wellcome Trust grant 106292/Z/14/Z (A.C.H., P.V., I.Z., and V.S.); Wellcome Trust Clinical Research Career Development Fellowship 220589/Z/20/Z (Y.W.); and UK COVID-Immunology-Consortium grant C33499/A20265 (A.C.H.)
Funding Information:
We thank all patients and blood donors who participated in this study, as well as the medical and research teams at Guy’s and St. Thomas’ Hospitals. Schema figures were created with BioRender.com. We likewise thank our colleagues for discussions and for their support. This study was supported by a Cancer Research Institute Irvington Fellowship (D.R.M.); Cancer Research UK (CRUK) Cancer ImmunoTherapy Accelerator (A.C.H., I.D.M.D.B.); CRUK City of London Major Cancer Centre studentship C604/A27440 (M.J.); European Molecular Biology Organization Long-term Fellowship 198-2018 (M.M.R.); Francis Crick Institute, which receives core funding from CRUK (grant FC001093), Medical Research Council (MRC) grant FC001093, and the Wellcome Trust (grant FC001093; A.C.H., L. Monin, and F.C.); John Black Charitable Foundation (A.C.H.); King’s Together Rapid COVID-19 Call Award (K.J.D.); King’s Together Seed Fund (A.C.H.); MRC King’s College London Doctoral Training Partnership in Biomedical Sciences grant MR/N013700/1 (C.G., S.G.); National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship (A.D. and Y.W.); NIHR Biomedical Research Centre for the Infectious Diseases Biobank (J.C. and C.M.); Rosetrees Trust (A.C.H.); Wellcome Trust grant 106292/Z/14/Z (A.C.H., P.V., I.Z., and V.S.); Wellcome Trust Clinical Research Career Development Fellowship 220589/Z/20/Z (Y.W.); and UK COVID-Immunology-Consortium grant C33499/A20265 (A.C.H.)
Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.
PY - 2022/8/23
Y1 - 2022/8/23
N2 - Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) β and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRβ and TCRδ loci, including some TCRβ sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.
AB - Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) β and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRβ and TCRδ loci, including some TCRβ sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.
KW - adaptive immune responses
KW - antigen-receptor repertoires
KW - immunoPETE
KW - next-generation sequencing
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85135769074&partnerID=8YFLogxK
U2 - 10.1073/pnas.2201541119
DO - 10.1073/pnas.2201541119
M3 - Article
C2 - 35943978
AN - SCOPUS:85135769074
SN - 0027-8424
VL - 119
SP - e2201541119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 34
M1 - e2201541119
ER -
