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Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor

Journal article
Authors Lei Wang
Erxia Shen
Lin Luo
Hardis Rabe
Qin Wang
Jie Yin
Xueying Yang
Wenquan Liu
Jessica M. Sido
Hidetoshi Nakagawa
Lin Ao
Hye Jung Kim
Harvey Cantor
Jianmei W. Leavenworth
Published in Cell Reports
Volume 29
Issue 7
Pages 1848-1861.e6
Publication year 2019
Published at Institute of Biomedicine, Department of Infectious Medicine
Pages 1848-1861.e6
Language en
Links https://doi.org/10.1016/j.celrep.20...
Keywords Blimp1, follicular helper T cells, follicular regulatory T cells, germinal center positioning, germinal center response, humoral tolerance, regulatory T cells, T lineage stability FR
Subject categories Cell and Molecular Biology, Immunology in the medical area

Abstract

© 2019 The Author(s) Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ TFR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in TFR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of TFR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient TFR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated TFR homing into the GC. These findings uncover a Blimp1-dependent TFR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry.

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