Abstract
Functional avidity is supposed to critically shape the quality of immune responses, thereby influencing host protection against infectious agents including SARS-CoV-2. Here we show that after human SARS-CoV-2 vaccination, a large portion of high-avidity spike-specific CD4+ T cells lost CD3 expression after in vitro activation. The CD3– subset was enriched for cytokine-positive cells, including elevated per-cell expression levels, and showed increased polyfunctionality. Assessment of key metabolic pathways by flow cytometry revealed that superior functionality was accompanied by a shift toward fatty acid synthesis at the expense of their oxidation, whereas glucose transport and glycolysis were similarly regulated in SARS-CoV-2–specific CD3– and CD3+ subsets. As opposed to their CD3+ counterparts, frequencies of vaccine-specific CD3– T cells positively correlated with both the size of the naive CD4+ T cell pool and vaccine-specific IgG levels. Moreover, their frequencies negatively correlated with advancing age and were impaired in patients under immunosuppressive therapy. Typical recall antigen–reactive T cells showed a comparable segregation into functionally and metabolically distinct CD3+ and CD3– subsets but were quantitatively maintained upon aging, likely due to earlier recruitment in life. In summary, our data identify CD3– T helper cells as correlates of high-quality immune responses that are impaired in at-risk populations.
Authors
Arne Sattler, Stefanie Gamradt, Vanessa Proß, Linda Marie Laura Thole, An He, Eva Vanessa Schrezenmeier, Katharina Jechow, Stefan M. Gold, Sören Lukassen, Christian Conrad, Katja Kotsch
Graphical abstract
