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

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

doi:10.3389/fimmu.2021.791100

Abstract

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper 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. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-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.

Highlights

Upon infection or vaccination / immunization germinal centers (GCs) form within the B-cell follicles of secondary lymphoid organs
We show here that NFATc1/aA and B lymphocyte-induced maturation protein-1 (Blimp-1) are both essential for T-follicular regulatory (TFR) generation and function, but intertwined in a system of checks and balances (Figure S9)
NFATc1/aA promotes CXCR5 expression otherwise repressed by Blimp-1 through recognizing neighboring response elements in promoter and enhancer as well as via protein-protein interaction with Blimp-1 itself

Summary

Introduction

Upon infection or vaccination / immunization germinal centers (GCs) form within the B-cell follicles of secondary lymphoid organs. During a germinal center response (GCR), T cell-dependent B-cell differentiation orchestrates the production of high-affinity antibodies of the IgG, IgA and/or IgE isotypes. This includes affinity maturation through clonal expansion and selection, somatic hypermutation of immunoglobulin gene variable regions (SHM), and class-switch recombination (CSR). To facilitate repositioning from T-cell zones into B-cell follicles, TFH cells depend on the expression of the chemokine receptor CXCR5 [3, 4]. CXCR5+ B and T cells follow a gradient of the chemokine CXCL13, which is the selective chemoattractant and mainly produced by follicular stromal cells [5]. There might be other ways to enter a follicle, i.e. passively in conjunction with B cells [6]

Methods

Results

Conclusion