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

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