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, noncanonical 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 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.
Highlights
Antibodies mediate protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic (1)
K18hACE2 Bcl6fl/fl mediastinal LN (medLN) exhibited robust germinal center (GC) formation, with large clusters of activated (GL7+) B cells colocalizing with CD35+ follicular dendritic cell (FDC) networks and infiltrated by T cells (Fig. S2A), presumably T follicular helper (Tfh) cells
Validating the BASELINe analytical approach, selection strength was positive in the complementarity determining regions (CDRs) of BCRs from Bcl6fl/fl mice and negative in the framework regions (FWRs) (Fig. 4G). This is consistent with the fact that CDRs are the main determinants of antigen specificity and enriched in non-synonymous mutations, while FWRs generally serve as structural scaffolds, making them less tolerant of residue-altering mutations. Across both CDRs and FWRs, we found that the ratio of non-synonymous to synonymous mutations was significantly lower in S-specific IgG plasmablasts from Bcl6fl/flCd4Cre mice compared to Bcl6fl/fl mice (Fig. 4G), indicating that Tfh cells are required for positive selection of mutated B cell clones against SARS-CoV-2
Summary
Antibodies mediate protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic (1). T follicular helper (Tfh) cells are the conventional drivers of protective antibody responses, as they support immunoglobulin class switching, germinal center (GC)-based affinity maturation, and long-lived humoral immunity (2). Multiple studies have reported a correlation between circulating Tfh (cTfh) cells – in particular, type 1 CXCR3+CCR6− cTfh cells – and neutralizing antibody titers in COVID-19 patients (3). Findings of enhanced extrafollicular B cell responses associated with severe disease further suggest that non-canonical pathways of antibody production may be operative in these individuals (6, 8). A causal relationship between antibody provenance and disease severity cannot be established by existing human studies. It remains unclear whether antibodies produced through non-canonical pathways without Tfh cell help are protective against SARSCoV-2
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