Stability and progressive differentiation of TFR cells are intrinsically and extrinsically controlled by TFH programs.

Follicular regulatory T (TFR) cells restrain follicular helper T (TFH) cell-mediated B cell responses to optimize humoral immunity while limiting autoimmunity. Here we assessed the developmental dynamics of TFR cells. We found that TFR cells undergo progressive differentiation through progenitor, early effector and late effector stages. Late effector TFR cells possessed inherent instability, and could lose expression of FoxP3 to become ExTFR cells. Expression of effector TFH programs in TFR cells preceded instability, a process that was mediated by Tcf7. A subset of ExTFR could be redeemed by re-expression of FoxP3. Extrinsically, TFH cells enhanced late effector TFR cell differentiation by diverting cells away from a default Prdm1/Blimp-1 fate to express Bcl6. Together, these data indicate that TFR cells are a dynamic and plastic cell subset, the differentiation of which is controlled by intrinsic and extrinsic programs that work together to form a feedback loop to control humoral immunity.