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.
Lee et al. (Tue,) studied this question.