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

Jun Siong Low, Daniela Vaqueirinho, Federico Mele, Mathilde Foglierini, Josipa Jerak, Michela Perotti, David Jarrossay, Sandra Jovic, Laurent Perez, Rosalia Cacciatore, Tatiana Terrot, Alessandra Franzetti Pellanda, Maira Biggiogero, Christian Garzoni, Paolo Ferrari, Alessandro Ceschi, Antonio Lanzavecchia, Federica Sallusto, Antonino Cassotta

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1336-1341
Number of pages6
Issue number6548
Publication statusPublished - Jun 18 2021

ASJC Scopus subject areas

  • General


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