TNFα-producing CD4 ⁺ T cells dominate the SARS-CoV-2-specific T cell response in COVID-19 outpatients and are associated with durable antibodies

SARS-CoV-2-specific CD4 ⁺ T cells are likely important in immunity against COVID-19, but our understanding of CD4 ⁺ longitudinal dynamics following infection and specific features that correlate with the maintenance of neutralizing antibodies remains limited. We characterized SARS-CoV-2-specific CD4 ⁺ T cells in a longitudinal cohort of 109 COVID-19 outpatients. The quality of the SARS-CoV-2-specific CD4 ⁺ response shifted from cells producing IFNγ to TNFα ⁺ from five days to four months post-enrollment, with IFNγ ^- IL21 ^- TNFα ⁺ CD4 ⁺ T cells the predominant population detected at later timepoints. Greater percentages of IFNγ ^- IL21 ^- TNFα ⁺ CD4 ⁺ T cells on day 28 correlated with SARS-CoV-2 neutralizing antibodies measured seven months post-infection (ρ=0.4, P=0.01). mRNA vaccination following SARS-CoV-2 infection boosted both IFNγ and TNFα producing, spike protein-specific CD4 ⁺ T cells. These data suggest that SARS-CoV-2-specific, TNFα-producing CD4 ⁺ T cells may play an important role in antibody maintenance following COVID-19.