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

Cell Rep. 2019 Nov 12;29(7):1848-1861.e6. doi: 10.1016/j.celrep.2019.10.012.


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.

Keywords: Blimp1; T(FR) lineage stability; follicular helper T cells; follicular regulatory T cells; germinal center positioning; germinal center response; humoral tolerance; regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation / immunology*
  • Germinal Center / cytology
  • Germinal Center / immunology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Mice
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1 / genetics
  • Positive Regulatory Domain I-Binding Factor 1 / immunology*
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / immunology
  • Receptors, CXCR5 / genetics
  • Receptors, CXCR5 / immunology
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*


  • CXCR5 protein, mouse
  • Ccr7 protein, mouse
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Prdm1 protein, mouse
  • Receptors, CCR7
  • Receptors, CXCR5
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • interleukin-23 receptor, mouse
  • Positive Regulatory Domain I-Binding Factor 1