AbstractT-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 21 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mount at least one CD4 T-cell response, and 48% of individuals mount detectable SARS-CoV-2-specific peripheral T follicular helper cells (pTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific pTfh responses across all three protein specificities correlate with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, pTfh responses increase in frequency and magnitude in convalescence, and robust responses with magnitudes greater than 5% were detected only at the second convalescent visit, an average of 38 days post-symptom onset. These data deepen our understanding of antigen-specific pTfh responses in SARS-CoV-2 infection, suggesting that M and N protein-specific pTfh may also assist in the development of neutralizing antibodies and that pTfh response formation may be delayed in SARS-CoV-2 infection.Author SummarySince December 2019, the Coronavirus Disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. Most currently licensed vaccines are understood to protect against infection by inducing neutralizing antibodies. As such, ongoing COVID-19 vaccine trials have focused on antibody neutralization as a primary immunologic endpoint. It is well established that T follicular helper cells are essential to the development of neutralizing antibodies and that a subset of these cells, peripheral T follicular helper cells (pTfh), can be studied in the blood. However, little is known about Tfh responses mounted in SARS-CoV-2 infection. Here, we studied pTfh to three major structural proteins in individuals recovered from COVID-19. We find that SARS-CoV-2-specific pTfh frequencies correlate with neutralizing antibody responses, especially those directed against the spike protein. We also find that pTfh responses to SARS-CoV-2 increase over time. Our findings suggest that pTfh responses against proteins other than the spike protein may contribute to the development of neutralizing antibodies and suggests that formation of pTfh responses in SARS-CoV-2 infection may be delayed.
Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells