SARS-CoV-2 epitope-specific CD4+ memory T cell responses across COVID-19 disease severity and antibody durability

CD4+ T cells are central to long-term immunity against viruses through the functions of T helper 1 (TH1) and T follicular helper (TFH) cell subsets. To better understand the role of these subsets in coronavirus disease 2019 (COVID-19) immunity, we conducted a longitudinal study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific CD4+ T cell and antibody responses in convalescent individuals who seroconverted during the first wave of the pandemic in Boston, MA, USA, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope–specific CD4+ T cells using peptide and major histocompatibility complex class II (pMHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most individuals compared with prepandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating TFH (cTFH) and TH1 cells among SARS-CoV-2–specific cells. Analysis of SARS-CoV-2–specific CD4+ T cells responses in a subset of individuals with sustained anti-S antibody responses after viral clearance also revealed an increased proportion of memory cTFH cells. Our findings indicate that efficient early disease control also predicts favorable long-term adaptive immunity. Description The proportion of cTFH within SARS-CoV-2–specific cells was decreased in severe disease and increased in sustained antibody producers.

Michael D Healy | Kelsey K. Finn | Han Liu | M. Carrington | K. Flaherty | Xu G. Yu | D. Wesemann | G. Alter | M. Lichterfeld | Fatema Z. Chowdhury | D. Lingwood | S. Pillai | C. O’Callaghan | David Golan | A. Balazs | A. Luster | Kelly Judge | J. Moon | Julia Bals | Grace Holland | A. Griffin | Y. Yuki | Maureen P. Martin | D. Drew | Ryan W. Nelson | J. Fallon | A. Michell | M. Dougan | Nishant K. Singh | Yuting Lu | Yuezhou Chen | Y. Bartsch | M. Ghebremichael | J. Boucau | Pilar García-Broncano | Daniel S. Shin | M. Barbash | Xiaodong Lian | Bruce Walker | M. Carrington | K. Sheppard | J. Flannery | Daniel P. Worrall | N. Jilg | A. Sharpe | Xiaoming Sun | A. Zhu | Andrew Chan | E. Gettings | Kevin B. Einkauf | Joshua M. Chevalier | K. Armstrong | C. Hartana | Colline Wong | A. Rosenthal | K. Lefteri | Matt Osborn | Chenyan Jiang | P. Kaplonek | Marshall Karpell | Jinqing Liu | Yelizaveta Rassadkina | Kyra W. Seiger | Libera Sessa | S. Shin | Weiwei Sun | Hannah Ticheli | P. Allen | E. Lam | C. Sharr | J. Braley | Peggy S. Lai | Jonathan Z Li | Z. Manickas-Hill | R. McNamara | S. Nelson | Olivia L. Venezia | R. Majerus | Betelihem A Abayneh | Diane Antille | Siobhan Boyce | Karen Branch | Katherine Broderick | J. Carney | G. Daley | Susan P. Davidson | Ashley Elliman | Liz Fedirko | Pamela J. Forde | S. Grimmel | Kathleen A. Grinke | K. Hall | H. Heller | Deborah Henault | Chantal Kayitesi | V. LaValle | Sarah Luthern | Natasha Ly | J. Marchewka | Brittani Martino | Ilan Millstrom | Noah Miranda | Christian Nambu | Marjorie Noone | Christine Ommerborn | Lois Chris Pacheco | Nicole Phan | F. A. Porto | Alexandra Reissis | Francis Ruzicka | E. Ryan | K. Selleck | Sue Slaughenhaupt | Elizabeth Suschana | Alicja Trocha-Piechocka | Vivine Wilson | Edward Demers | Jonathan Z. Li | Ashlin R. Michell | Jonathan K. Fallon | Andrew T. Chan | B. A. Abayneh | Susan P Davidson | Pamela J Forde | N. Ly | Xu G. Yu | Xu G. Yu

[1]  A. Wald,et al.  Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals , 2021, PLoS pathogens.

[2]  D. Jarrossay,et al.  Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2 , 2021, Science.

[3]  A. Sette,et al.  Differential T-Cell Reactivity to Endemic Coronaviruses and SARS-CoV-2 in Community and Health Care Workers , 2021, The Journal of infectious diseases.

[4]  W. Greene,et al.  Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19 , 2021, Cell Reports.

[5]  Gavin J. D. Smith,et al.  Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients , 2021, Cell Reports.

[6]  F. Ay,et al.  Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells , 2021, Science Immunology.

[7]  Bjoern Peters,et al.  Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection , 2021, Science.

[8]  C. Dutertre,et al.  Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection , 2020, bioRxiv.

[9]  P. Rosenstiel,et al.  Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19 , 2020, Immunity.

[10]  J. Jardine,et al.  SARS-CoV-2 Antibody Responses Are Correlated to Disease Severity in COVID-19 Convalescent Individuals. , 2020, Journal of immunology.

[11]  M. Malim,et al.  Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans , 2020, Nature Microbiology.

[12]  R. V. van Lier,et al.  Divergent SARS‐CoV‐2‐specific T‐ and B‐cell responses in severe but not mild COVID‐19 patients , 2020, European journal of immunology.

[13]  H. Rammensee,et al.  SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition , 2020, Nature immunology.

[14]  M. Fehlings,et al.  Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5+ CD4+ T cells after yellow fever vaccination , 2020, Scientific Reports.

[15]  Steven M. Holland,et al.  Autoantibodies against type I IFNs in patients with life-threatening COVID-19 , 2020, Science.

[16]  Jacques Fellay,et al.  Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 , 2020, Science.

[17]  J. Greenbaum,et al.  Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity , 2020, Cell.

[18]  Henry A. Utset,et al.  SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike , 2020, bioRxiv.

[19]  P. Sopp,et al.  Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19 , 2020, Nature Immunology.

[20]  Kelsey K. Finn,et al.  Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19 , 2020, Cell.

[21]  L. Carter,et al.  Functional SARS-CoV-2-specific immune memory persists after mild COVID-19 , 2020, medRxiv.

[22]  S. Mallal,et al.  Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans , 2020, Science.

[23]  U. Reimer,et al.  SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19 , 2020, Nature.

[24]  Eric Song,et al.  Longitudinal analyses reveal immunological misfiring in severe COVID-19 , 2020, Nature.

[25]  Sasikanth Manne,et al.  Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications , 2020, Science.

[26]  Martin Linster,et al.  SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls , 2020, Nature.

[27]  Morten Nielsen,et al.  Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19 , 2020, Cell.

[28]  X. Tang,et al.  Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections , 2020, Nature Medicine.

[29]  D. Lauffenburger,et al.  Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production , 2020, Cell.

[30]  J. Greenbaum,et al.  Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals , 2020, Cell.

[31]  Li Yang,et al.  Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis , 2020, International Journal of Infectious Diseases.

[32]  Y. Hu,et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China , 2020, The Lancet.

[33]  Jennifer G. Abelin,et al.  Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. , 2019, Immunity.

[34]  Alessandro Sette,et al.  The Immune Epitope Database (IEDB): 2018 update , 2018, Nucleic Acids Res..

[35]  M. Pepper,et al.  Generation of Allergen-Specific Tetramers for a Murine Model of Airway Inflammation. , 2018, Methods in molecular biology.

[36]  Peipei Xu,et al.  A systemic review and meta-analysis , 2017 .

[37]  R. Baric,et al.  Airway Memory CD4+ T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses , 2016, Immunity.

[38]  Alessandro Sette,et al.  Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. , 2013, Immunity.

[39]  A. Luster,et al.  Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4 , 2013, The Journal of experimental medicine.

[40]  P. Dash,et al.  Quantitative impact of thymic selection on Foxp3+ and Foxp3− subsets of self-peptide/MHC class II-specific CD4+ T cells , 2011, Proceedings of the National Academy of Sciences.

[41]  Marion Pepper,et al.  Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. , 2007, Immunity.