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

Abstract

Follicular regulatory T (T_FR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain T_FR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3⁺ T_FR cells is essential for T_FR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in T_FR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of T_FR 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 T_FR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated T_FR homing into the GC. These findings uncover a Blimp1-dependent T_FR 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.