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.

Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56^neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56^dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56^neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56^dim NK cells. Higher frequencies of CD56^neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.