Patients With Mild COVID-19 Exhibit Low Functional Avidity of SARS-CoV-2 Membrane Protein-Reactive CD4⁺ T Cells

Herein, we found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-unexposed individuals exhibited an increased frequency of CD4⁺ T cells against SARS-CoV-2 membrane (M) protein, suggesting that SARS-CoV-2 M-reactive cells may be primed by previous infection with common cold coronaviruses (CCCoVs). We confirmed that CCCoV M-reactive CD4⁺ T cells cross-recognize SARS-CoV-2 M in unexposed individuals. Among coronavirus disease 2019 (COVID-19) convalescents and unexposed individuals, SARS-CoV-2 M-reactive CD4⁺ T cells exhibited significantly lower functional avidity than CD4⁺ T cells reactive to other viruses. Importantly, convalescents from mild COVID-19 had SARS-CoV-2 M-reactive CD4⁺ T cells with significantly lower functional avidity than convalescents from severe COVID-19. The current data suggest that pre-existing CCCoV M-specific memory CD4⁺ T cells may contribute to controlling SARS-CoV-2 infection by cross-reactivity, leading to mild disease but leaving memory cells with low functional avidity to SARS-CoV-2 M due to incomplete homology. These data provide indirect evidence that pre-existing cross-reactive CD4⁺ T cells contribute to protection from severe COVID-19.