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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4⁺ T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4⁺ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4⁺ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4⁺ response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ^-IL-21^-TNF-α⁺ CD4⁺ T cells the predominant population detected at later time points. Greater percentages of IFNγ^-IL-21^-TNF-α⁺ CD4⁺ T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4⁺ T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4⁺ T cells may play an important role in antibody maintenance following COVID-19.