Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19

Highlights

• Germinal centers are lost in lymph nodes and spleens in acute COVID-19

• Bcl-6⁺ GC B cells and Bcl-6⁺ T follicular helper cells are markedly diminished

• Abundant T_H1 cells and aberrant TNF-α production are seen in COVID-19 lymph nodes

• SARS-CoV-2-specific activated B cells accumulate in the blood of patients

Summary

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6⁺ germinal center B cells but preservation of AID⁺ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6⁺ T_FH cell differentiation together with an increase in T-bet⁺ T_H1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6⁺ T_FH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.