Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4+ T cell recognition

CD4 + T cells are essential for protection against viruses, including SARS-CoV-2. The sensitivity of CD4 + T cells to mutations in SARS-CoV-2 variants of concern (VOCs) is poorly understood. Here, we isolated 159 SARS-CoV-2-specific CD4 + T cell clones from healthcare workers previously infected with wild-type SARS-CoV-2 (D614G) and defined 21 epitopes in spike, membrane and nucleoprotein. Lack of CD4 + T cell cross-reactivity between SARS-CoV-2 and endemic beta-coronaviruses suggested these responses arose from naïve rather than pre-existing cross-reactive coronavirus-specific T cells. Of the 17 epitopes located in the spike protein, 10 were mutated in VOCs and CD4 + T cell clone recognition of 7 of them was impaired, including 3 of the 4 epitopes mutated in omicron. Our results indicated that broad targeting of epitopes by CD4 + T cells likely limits evasion by current VOCs. However, continued genomic surveillance is vital to identify new mutations able to evade CD4 + T cell immunity. Based on the identification of CD4 + T cell clones specific for distinct epitopes in the SARS-CoV-2 proteins, Long and colleagues characterize how mutations in these epitopes lead to loss of recognition by the CD4 + T cells elicited by natural infection or vaccination.