AUTHOR=Koenig Anika , Vaeth Martin , Xiao Yin , Chiarolla Cristina M. , Erapaneedi Raghu , Klein Matthias , Dietz Lena , Hundhausen Nadine , Majumder Snigdha , Schuessler Felix , Bopp Tobias , Klein-Hessling Stefan , Rosenwald Andreas , Berberich Ingolf , Berberich-Siebelt Friederike 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.791100

DOI=10.3389/fimmu.2021.791100

ISSN=1664-3224

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