NFATc1/αA and Blimp-1 support the follicular and effector phenotype of Tregs

CD4+CXCR5+Foxp3+ T follicular regulatory (TFR) cells control the germinal center responses. Like follicular helper T-cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. NFATc1/αA is necessary to overcome TFR-expressed B lymphocyte-induced maturation protein (Blimp-1), which can directly repress Cxcr5. Blimp-1 then 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, which strengthens the follicular development of Tregs, but bears the inherent risk of causing an ex-Treg phenotype. Prdm1gfp mice were crossed to Nfatc1fl/fl.FIC, Nfatc1caaA.FIC and Nfatc1caaA.Prdm1fl/fl.FIC mouse lines and TFR cells sorted as CD4+B220―GFP+CXCR5+GITRhi cells 10 days post NP-KLH immunization.