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CD4 + CXCR5 + Foxp3 +  T-follicular regulatory (T FR ) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of   N uclear  F actor of  A ctivated  T -cells  c1  , predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of T FR  cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a T FR  migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, T FR  cells express B   ly mphocyte- i nduced  m aturation  p rotein-1   (Blimp-1). Blimp-1 can directly repress  Cxcr5  and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to  Cxcr5  by protein-protein interaction and by those means cooperates with NFATc1 for  Cxcr5  transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.

NFATc1/αA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs