Heterogeneity of T follicular regulatory cells: exploring their expanding ontogeny and differentiation pathways

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⁺ nTfr), before transitioning into a more mature CD25-negative state within the GC (CD25^- nTfr). Conversely, the induced route (iTfr) includes Tfr cells that arise alongside nTfr cells but originate from peripheral Tregs or CD25-expressing Tfh cells, in addition to a late-GC subset (late Tfr) that emerges through the expression of FoxP3 by Tfh cells. The identification of circulating Tfr cells (cTfr) in peripheral blood, especially useful for studying immune dysregulation in humans, provides insights into their systemic roles and potential as biomarkers for immune dysfunction in different clinical scenarios. While it becomes evident that Tfr cells exhibit a heterogeneous nature, a deeper understanding of their distinct subsets could pave the way for targeted immunomodulatory strategies in the development of novel vaccines and therapeutics. This review provides a comprehensive overview of Tfr cell diversity, exploring their ontogeny, functional roles, and impact on immune homeostasis and disease.