SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

SJTRC Study Team

doi:10.1016/j.cell.2021.12.026

SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

SJTRC Study Team

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4⁺ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4⁺ T (T_FH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node T_FH. Mining of the responding T_FH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1^∗04-restricted response to S_167–180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific T_FH cells peak one week after the second immunization, S-specific T_FH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust T_FH cell responses play in establishing long-term immunity by this efficacious human vaccine.

Original language	English
Pages (from-to)	603-613.e15
Journal	Cell
Volume	185
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2021.12.026
State	Published - Feb 17 2022

Keywords

CD4 T cell
COVID-19
SARS-CoV-2
T follicular helper cell
TCR repertoire
human immunology
lymph node
mRNA vaccination

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10.1016/j.cell.2021.12.026

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@article{e3e2f72b221242c8a1f0668dc7c19899,

title = "SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans",

abstract = "SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167–180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.",

keywords = "CD4 T cell, COVID-19, SARS-CoV-2, T follicular helper cell, TCR repertoire, human immunology, lymph node, mRNA vaccination",

author = "{SJTRC Study Team} and Mudd, {Philip A.} and Minervina, {Anastasia A.} and Pogorelyy, {Mikhail V.} and Turner, {Jackson S.} and Wooseob Kim and Elizaveta Kalaidina and Jan Petersen and Schmitz, {Aaron J.} and Tingting Lei and Alem Haile and Kirk, {Allison M.} and Mettelman, {Robert C.} and Crawford, {Jeremy Chase} and Nguyen, {Thi H.O.} and Rowntree, {Louise C.} and Elisa Rosati and Richards, {Katherine A.} and Sant, {Andrea J.} and Klebert, {Michael K.} and Teresa Suessen and Middleton, {William D.} and Estepp, {Jeremie H.} and Stacey Schultz-Cherry and McGargill, {Maureen A.} and Aditya Gaur and James Hoffman and Motomi Mori and Li Tang and Elaine Tuomanen and Richard Webby and Hayden, {Randall T.} and Hana Hakim and Hijano, {Diego R.} and Allison, {Kim J.} and Allen, {E. Kaitlynn} and Resha Bajracharya and Walid Awad and {Van de Velde}, {Lee Ann} and Clark, {Brandi L.} and Wilson, {Taylor L.} and Aisha Souquette and Ashley Castellaw and Dallas, {Ronald H.} and Ashleigh Gowen and Fabrizio, {Thomas P.} and Lin, {Chun Yang} and Brice, {David C.} and Sean Cherry and Roubidoux, {Ericka Kirkpatrick} and Valerie Cortez and Pamela Freiden and Nicholas Wohlgemuth and Kendall Whitt and Joshua Wolf and Teefey, {Sharlene A.} and O'Halloran, {Jane A.} and Presti, {Rachel M.} and Katherine Kedzierska and Jamie Rossjohn and Thomas, {Paul G.} and Ellebedy, {Ali H.}",

note = "Funding Information: The authors would like to thank the study participants for their invaluable contribution to this work. We also thank Greig Lennon from St. Jude Immunology flow core for his help with FACS, Hartwell Center at St. Jude Children's Research Hospital for high-throughput sequencing, and Carmen Llerna for assistance in HLA-DP4 protein purification. This study was funded in part by the Washington University Institute for Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) (P.A.M.). J.R. is supported by an Australian Research Council Laureate Fellowship. K.K. was supported by the NHMRC Leadership Investigator Fellowship (#1173871), and T.H.O.N. was supported by the NHMRC Emerging Leadership Level 1 Investigator Fellowship (#1194036). This work was funded by ALSAC at St. Jude; the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) contract number 75N93019C00052 (P.G.T. and K.K.); the St. Jude Center of Excellence for Influenza Research and Surveillance (P.G.T.) contract number HHSN272201400006C; and the St. Jude Center of Excellence for Influenza Research and Response (P.G.T.) contract numbers 75N93021C00016, U01AI150747, U01AI144616-02S1, and R01AI136514 (P.G.T.). The Ellebedy laboratory was supported by NIAID grants U01AI141990 and U01AI150747, NIAID Centers of Excellence for Influenza Research and Surveillance contracts HHSN272201400006C and HHSN272201400008C, and by NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Conceptualization: P.A.M. A.A.M. M.V.P. P.G.T. and A.H.E.; methodology: P.A.M. A.A.M. M.V.P. J.S.T. J.P. J.C.C. M.K.K. S.A.T. J.A.O. R.M.P. P.G.T. and A.H.E.; investigation: P.A.M. A.A.M. M.V.P. J.S.T. W.K. E.K. J.P. A.J. Schmitz, T.L. A.H. A.M.K. R.C.M. J.C.C. T.H.O.N. L.C.R. E.R. K.A.R. A.J. Sant, T.S. W.D.M. and S.A.T.; formal analysis: P.A.M. A.A.M. M.V.P. and J.C.C.; visualization: P.A.M. A.A.M. M.V.P. and R.C.M.; resources: SJTRC Study Team; Data curation: J.C.C. J.W. and SJTRC Study Team; funding acquisition: P.A.M. P.G.T. and A.H.E.; supervision: P.A.M. S.A.T. J.A.O. R.M.P. K.K. J.R. P.G.T. and A.H.E.; writing – original draft: P.A.M. A.A.M. and M.V.P.; writing – review & editing: all co-authors. The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to the data presented in the current study from Emergent BioSolutions and from AbbVie. A.H.E. has received consulting payments from Mubadala Investment Company, InBios International, and Fimbrion Therapeutics and is the founder of ImmuneBio Consulting. P.G.T. has consulted and/or received honoraria and travel support from Illumina, Johnson and Johnson, and 10X Genomics. P.G.T. serves on the Scientific Advisory Board of Immunoscape and Cytoagents. The authors have applied for patents covering some aspects of these studies. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. Funding Information: The authors would like to thank the study participants for their invaluable contribution to this work. We also thank Greig Lennon from St. Jude Immunology flow core for his help with FACS, Hartwell Center at St. Jude Children{\textquoteright}s Research Hospital for high-throughput sequencing, and Carmen Llerna for assistance in HLA-DP4 protein purification. This study was funded in part by the Washington University Institute for Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) (P.A.M.). J.R. is supported by an Australian Research Council Laureate Fellowship. K.K. was supported by the NHMRC Leadership Investigator Fellowship (# 1173871 ), and T.H.O.N. was supported by the NHMRC Emerging Leadership Level 1 Investigator Fellowship (# 1194036 ). This work was funded by ALSAC at St. Jude; the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) contract number 75N93019C00052 (P.G.T. and K.K.); the St. Jude Center of Excellence for Influenza Research and Surveillance (P.G.T.) contract number HHSN272201400006C ; and the St. Jude Center of Excellence for Influenza Research and Response (P.G.T.) contract numbers 75N93021C00016 , U01AI150747 , U01AI144616-02S1 , and R01AI136514 (P.G.T.). The Ellebedy laboratory was supported by NIAID grants U01AI141990 and U01AI150747 , NIAID Centers of Excellence for Influenza Research and Surveillance contracts HHSN272201400006C and HHSN272201400008C , and by NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051 . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2022",

month = feb,

day = "17",

doi = "10.1016/j.cell.2021.12.026",

language = "English",

volume = "185",

pages = "603--613.e15",

journal = "Cell",

issn = "0092-8674",

number = "4",

}

TY - JOUR

T1 - SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

AU - SJTRC Study Team

AU - Mudd, Philip A.

AU - Minervina, Anastasia A.

AU - Pogorelyy, Mikhail V.

AU - Turner, Jackson S.

AU - Kim, Wooseob

AU - Kalaidina, Elizaveta

AU - Petersen, Jan

AU - Schmitz, Aaron J.

AU - Lei, Tingting

AU - Haile, Alem

AU - Kirk, Allison M.

AU - Mettelman, Robert C.

AU - Crawford, Jeremy Chase

AU - Nguyen, Thi H.O.

AU - Rowntree, Louise C.

AU - Rosati, Elisa

AU - Richards, Katherine A.

AU - Sant, Andrea J.

AU - Klebert, Michael K.

AU - Suessen, Teresa

AU - Middleton, William D.

AU - Estepp, Jeremie H.

AU - Schultz-Cherry, Stacey

AU - McGargill, Maureen A.

AU - Gaur, Aditya

AU - Hoffman, James

AU - Mori, Motomi

AU - Tang, Li

AU - Tuomanen, Elaine

AU - Webby, Richard

AU - Hayden, Randall T.

AU - Hakim, Hana

AU - Hijano, Diego R.

AU - Allison, Kim J.

AU - Allen, E. Kaitlynn

AU - Bajracharya, Resha

AU - Awad, Walid

AU - Van de Velde, Lee Ann

AU - Clark, Brandi L.

AU - Wilson, Taylor L.

AU - Souquette, Aisha

AU - Castellaw, Ashley

AU - Dallas, Ronald H.

AU - Gowen, Ashleigh

AU - Fabrizio, Thomas P.

AU - Lin, Chun Yang

AU - Brice, David C.

AU - Cherry, Sean

AU - Roubidoux, Ericka Kirkpatrick

AU - Cortez, Valerie

AU - Freiden, Pamela

AU - Wohlgemuth, Nicholas

AU - Whitt, Kendall

AU - Wolf, Joshua

AU - Teefey, Sharlene A.

AU - O'Halloran, Jane A.

AU - Presti, Rachel M.

AU - Kedzierska, Katherine

AU - Rossjohn, Jamie

AU - Thomas, Paul G.

AU - Ellebedy, Ali H.

N1 - Funding Information: The authors would like to thank the study participants for their invaluable contribution to this work. We also thank Greig Lennon from St. Jude Immunology flow core for his help with FACS, Hartwell Center at St. Jude Children's Research Hospital for high-throughput sequencing, and Carmen Llerna for assistance in HLA-DP4 protein purification. This study was funded in part by the Washington University Institute for Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) (P.A.M.). J.R. is supported by an Australian Research Council Laureate Fellowship. K.K. was supported by the NHMRC Leadership Investigator Fellowship (#1173871), and T.H.O.N. was supported by the NHMRC Emerging Leadership Level 1 Investigator Fellowship (#1194036). This work was funded by ALSAC at St. Jude; the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) contract number 75N93019C00052 (P.G.T. and K.K.); the St. Jude Center of Excellence for Influenza Research and Surveillance (P.G.T.) contract number HHSN272201400006C; and the St. Jude Center of Excellence for Influenza Research and Response (P.G.T.) contract numbers 75N93021C00016, U01AI150747, U01AI144616-02S1, and R01AI136514 (P.G.T.). The Ellebedy laboratory was supported by NIAID grants U01AI141990 and U01AI150747, NIAID Centers of Excellence for Influenza Research and Surveillance contracts HHSN272201400006C and HHSN272201400008C, and by NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Conceptualization: P.A.M. A.A.M. M.V.P. P.G.T. and A.H.E.; methodology: P.A.M. A.A.M. M.V.P. J.S.T. J.P. J.C.C. M.K.K. S.A.T. J.A.O. R.M.P. P.G.T. and A.H.E.; investigation: P.A.M. A.A.M. M.V.P. J.S.T. W.K. E.K. J.P. A.J. Schmitz, T.L. A.H. A.M.K. R.C.M. J.C.C. T.H.O.N. L.C.R. E.R. K.A.R. A.J. Sant, T.S. W.D.M. and S.A.T.; formal analysis: P.A.M. A.A.M. M.V.P. and J.C.C.; visualization: P.A.M. A.A.M. M.V.P. and R.C.M.; resources: SJTRC Study Team; Data curation: J.C.C. J.W. and SJTRC Study Team; funding acquisition: P.A.M. P.G.T. and A.H.E.; supervision: P.A.M. S.A.T. J.A.O. R.M.P. K.K. J.R. P.G.T. and A.H.E.; writing – original draft: P.A.M. A.A.M. and M.V.P.; writing – review & editing: all co-authors. The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to the data presented in the current study from Emergent BioSolutions and from AbbVie. A.H.E. has received consulting payments from Mubadala Investment Company, InBios International, and Fimbrion Therapeutics and is the founder of ImmuneBio Consulting. P.G.T. has consulted and/or received honoraria and travel support from Illumina, Johnson and Johnson, and 10X Genomics. P.G.T. serves on the Scientific Advisory Board of Immunoscape and Cytoagents. The authors have applied for patents covering some aspects of these studies. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. Funding Information: The authors would like to thank the study participants for their invaluable contribution to this work. We also thank Greig Lennon from St. Jude Immunology flow core for his help with FACS, Hartwell Center at St. Jude Children’s Research Hospital for high-throughput sequencing, and Carmen Llerna for assistance in HLA-DP4 protein purification. This study was funded in part by the Washington University Institute for Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) (P.A.M.). J.R. is supported by an Australian Research Council Laureate Fellowship. K.K. was supported by the NHMRC Leadership Investigator Fellowship (# 1173871 ), and T.H.O.N. was supported by the NHMRC Emerging Leadership Level 1 Investigator Fellowship (# 1194036 ). This work was funded by ALSAC at St. Jude; the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) contract number 75N93019C00052 (P.G.T. and K.K.); the St. Jude Center of Excellence for Influenza Research and Surveillance (P.G.T.) contract number HHSN272201400006C ; and the St. Jude Center of Excellence for Influenza Research and Response (P.G.T.) contract numbers 75N93021C00016 , U01AI150747 , U01AI144616-02S1 , and R01AI136514 (P.G.T.). The Ellebedy laboratory was supported by NIAID grants U01AI141990 and U01AI150747 , NIAID Centers of Excellence for Influenza Research and Surveillance contracts HHSN272201400006C and HHSN272201400008C , and by NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051 . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2022/2/17

Y1 - 2022/2/17

N2 - SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167–180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.

AB - SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167–180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.

KW - CD4 T cell

KW - COVID-19

KW - SARS-CoV-2

KW - T follicular helper cell

KW - TCR repertoire

KW - human immunology

KW - lymph node

KW - mRNA vaccination

UR - http://www.scopus.com/inward/record.url?scp=85123021856&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.12.026

DO - 10.1016/j.cell.2021.12.026

M3 - Article

C2 - 35026152

AN - SCOPUS:85123021856

SN - 0092-8674

VL - 185

SP - 603-613.e15

JO - Cell

JF - Cell

IS - 4

ER -

SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans

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