Pairwise associations of the functional and phenotypical characteristics of SARS-CoV-2–responding CD4 cells identified 2 signatures: (a) activated cells exhibiting an early differentiated memory phenotype and preferentially secreting IL-2 and TNF-α, characteristic of COVID-19 patients, and (b) late differentiated memory cells with elevated GrB expression endowed with polyfunctional capacities predominantly observed in SARS-CoV-2–responsive CD4+ T cells from uninfected individuals (Figure 3C). Here, TNF is linked to COVID-19.