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

Abstract

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.