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

Abstract

Probing CD4 T cell immunity to SARS-CoV-2 A better understanding of CD4+ T cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to the design of effective next-generation vaccines. Low et al. defined and estimated the CD4+ T cell repertoire of convalescent COVID-19 patients. After sorting various CD4+ T cell subsets, they generated numerous T cell clones that reacted to the SARS-CoV-2 spike protein. In around a third of all clones and almost all individuals, the T cells recognized a small conserved immunodominant region within the spike protein receptor-binding domain (RBD). The researchers isolated T cell clones that broadly reacted to the spike protein of other coronaviruses, providing evidence for the recall of preexisting cross-reactive memory T cells after SARS-CoV-2 infection. Science, abg8985, this issue p. 1336 An analysis of T helper cell clones from COVID-19 patients reveals a conserved immunodominant region in the spike protein receptor-binding domain. 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.