T follicular regulatory (Tfr) cells have emerged as key mediators in controlling germinal center (GC) responses, preventing excessive immune activation and preserving self-tolerance. Initially thought to originate solely from thymic T regulatory cells (tTregs), recent findings reveal a more complex picture involving multiple differentiation pathways contributing to their heterogeneity. The natural route of differentiation comprises the most abundant subset, which originates from tTregs and retains the expression of CD25 (CD25