Follicular T cells optimize the germinal center response to SARS-CoV-2 protein vaccination in mice

Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find that Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC but do so by limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses, presenting a bimodal distribution of SHM. Together, these data demonstrate that GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.

Automated summary

This study reveals the roles of follicular helper T cells (Tfh cells) and follicular regulatory T cells (Tfr cells) in the germinal center (GC) reactions after SARS-CoV-2 spike protein vaccination. Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells, while Tfr cells control SHM and clonal diversity in the GC by limiting clonal competition.