Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2

Science. 2021 Jun 18;372(6548):1336-1341. doi: 10.1126/science.abg8985. Epub 2021 May 18.


The identification of CD4+ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19-recovered individuals a robust CD4+ T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346-S365 region comprising nested human leukocyte antigen DR (HLA-DR)- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • COVID-19 / immunology*
  • Coronavirus / immunology
  • Cross Reactions
  • Epitopes, T-Lymphocyte / immunology
  • Genes, T-Cell Receptor beta
  • HLA-DP Antigens / immunology
  • HLA-DR Antigens / immunology
  • Humans
  • Immunodominant Epitopes*
  • Immunologic Memory
  • Nucleocapsid Proteins / immunology
  • Protein Domains
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / immunology*
  • T Follicular Helper Cells / immunology
  • T-Lymphocyte Subsets / immunology


  • Epitopes, T-Lymphocyte
  • HLA-DP Antigens
  • HLA-DR Antigens
  • Immunodominant Epitopes
  • Nucleocapsid Proteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2