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

This is the authors' abstract. We don't add key points for this paper.

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.