Thymic T _REG -derived T follicular regulatory cells prevent catastrophic humoral autoimmunity in response to TLR7-driven inflammation

T follicular regulatory cells (T _FR ) are a follicle-resident subset of regulatory T cells (T _REG ) that limit germinal center (GC) responses and enforce humoral tolerance. Although T _FR 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 T _FR in preserving immune tolerance. Selective loss of T _FR 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 T _FR -sucicient mice but persisted in their absence. Mechanistically, T _FR limited the establishment and expansion of spontaneous GCs in response to inflammation, and responding T _FR displayed transcriptional, phenotypic, and clonal features of thymic T _REG . This suggests that whereas T _FH upregulate FoxP3 to shut down end-stage GCs, it is thymic T _REG -derived T _FR that safeguard GC integrity under inflammatory stress to prevent lethal autoimmunity.