T follicular regulatory cells (Tfr) are a follicle-resident subset of regulatory T cells (Treg) that limit germinal center (GC) responses and enforce humoral tolerance. Although Tfr are known to focus antibody responses to foreign antigens, how GC-specific regulation is maintained during inflammation remains unclear. Here, TLR7-driven inflammation unmasked a critical, non-redundant role for Tfr in preserving immune tolerance. Selective loss of Tfr caused severe autoimmunity and increased mortality, driven by inflammation-induced expansion of autoreactive B and T cell clones and epitope spreading. Autoreactivity resolved upon cessation of inflammation in Tfr-sufficient mice but persisted in their absence. Mechanistically, Tfr limited the establishment and expansion of spontaneous GCs in response to inflammation, and responding Tfr displayed transcriptional, phenotypic, and clonal features of thymic Treg. This suggests that whereas Tfh upregulate FoxP3 to shut down end-stage GCs, it is thymic Treg-derived Tfr that safeguard GC integrity under inflammatory stress to prevent lethal autoimmunity.
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