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Follicular regulatory T cells (T_FR cells) inhibit follicular helper T cell (T_FH cell)–mediated antibody production. The mechanisms by which T_FR cells exert their key immunoregulatory functions are largely unknown. Here we found that T_FR cells induced a distinct suppressive state in T_FH cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by T_FR cells was durable and persisted even in the absence of T_FR cells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome T_FR cell–mediated suppression and inhibited T_FR cells and stimulated B cells. By determining mechanisms of T_FR cell-mediated suppression, we have identified methods for modulating the function of T_FR cells and antibody production.