Cell reports. Medicine. 2022-06-21; 3.6: 100640.

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

van der Ploeg K, Kirosingh AS, Mori DAM, Chakraborty S, Hu Z, Sievers BL, Jacobson KB, Bonilla H, Parsonnet J, Andrews JR, Press KD, Ty MC, Ruiz-Betancourt DR, de la Parte L, Tan GS, Blish CA, Takahashi S, Rodriguez-Barraquer I, Greenhouse B, Singh U, Wang TT, Jagannathan P

PMID: 35588734


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 IFNγIL-21TNF-α CD4 T cells the predominant population detected at later time points. Greater percentages of IFNγIL-21TNF-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.