Abstract
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.