CD137 agonists in mice suppress germinal center responses by increasing the immunosuppressive activity of follicular regulatory T-cells

<jats:title>Abstract</jats:title> <jats:p>Humoral immune responses rely on germinal center (GC) reactions to generate long-lasting antibody responses with affinity maturation. CD137 (4-1BB) agonists are known to exert inhibitory effects on B-cell responses; however, the underlying mechanisms remain unclear. Here, we show that agonistic anti-CD137 monoclonal antibodies target multiple CD137-expressing cell types, including activated CD8⁺ T-cells, regulatory T-cells, follicular regulatory T-cells, and follicular dendritic cells. Anti-CD137 antibodies strongly disrupt GC reactions upon vaccination, preventing the development of anti-drug antibodies, and suppress ectopic B-cell responses within tumor-associated tertiary lymphoid structures in mice. Mechanistic analyses demonstrate that GC disruption occurs independently of IFN-γ, IL-12, and CD8⁺ T-cells, but is critically dependent on Foxp3⁺ T-cells. Combined transcriptomic profiling, immune phenotyping, and functional GC suppression assays reveal that anti-CD137 treatment increases the abundance and immunosuppressive activity of regulatory and follicular regulatory T-cells in vaccinated mice. Our results uncover the cellular basis of CD137-mediated suppression of humoral immunity and provide insight into rational combinatorial immunotherapeutic strategies incorporating CD137 agonists under active clinical development.</jats:p>