High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells

Chen, J. S.; Chow, R. D.; Song, E.; Mao, T.; Israelow, B.; Kamath, K.; Bozekowski, J.; Haynes, W. A.; Filler, R. B.; Menasche, B. L.; Wei, J.; Alfajaro, M. M.; Song, W.; Peng, L.; Carter, L.; Weinstein, J. S.; Gowthaman, U.; Chen, S.; Craft, J.; Shon, J. C.; Iwasaki, A.; Wilen, C. B.; Eisenbarth, S. C.

doi:10.1101/2021.06.10.447982

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bioRxiv · 10.1101/2021.06.10.447982

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells

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Abstract

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 as well as influenza A virus. Tfh-independent responses were mediated by a population we call lymph node (LN)-Th1 cells, which remain in the LN and interact with B cells outside of GCs to promote high-affinity but broad-spectrum antibodies. Strikingly, antibodies generated in the presence and absence of Tfh cells displayed similar neutralization potency against homologous SARS-CoV-2 as well as the B.1.351 variant of concern. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GCs and even compensate for GCs damaged by viral inflammation. One-Sentence SummaryComplementary pathways of antibody production mediate neutralizing responses to SARS-CoV-2.

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Chen, J. S., Chow, R. D., Song, E., Mao, T., Israelow, B., Kamath, K., Bozekowski, J., Haynes, W. A., Filler, R. B., Menasche, B. L., Wei, J., Alfajaro, M. M., Song, W., Peng, L., Carter, L., Weinstein, J. S., Gowthaman, U., Chen, S., Craft, J., Shon, J. C., Iwasaki, A., Wilen, C. B., Eisenbarth, S. C.. 2021-06-11. High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells. https://doi.org/10.1101/2021.06.10.447982

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