Pedersen, M. K. | bioRxiv Science

bioRxiv2026

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

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-sucicient 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.

immunology↗

bioRxiv2022

Germinal center block exacerbates extrafollicular responses and accelerates autoimmune disease progression in a murine lupus model

Many autoimmune diseases are characterized by germinal center (GC) derived affinity-matured, class-switched autoantibodies. Strategies to block GC formation and progression are currently being explored clinically, however, extrafollicular responses may also contribute to early events in autoimmunity. To investigate the relative contribution of these two pathways in autoimmune disease development, we leveraged a transgenic strategy to genetically block the GC pathway. Surprisingly, this accelerated extrafollicular responses and failed to curb autoimmune progression in two lupus models. In vitro, loss of the GC transcription factor Bcl-6 prevented cellular expansion and accelerated plasma cell differentiation, suggesting the in vivo phenotype was caused by rewiring of B cell intrinsic transcriptional programming. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Taken together, this emphasizes the extrafollicular pathway as a key contributor to autoimmune progression, and suggests that strategies aimed at blocking GCs should simultaneously target this pathway to avoid rerouting the pathogenic response. Highlights- A genetic GC block fails to prevent autoimmune progression in two lupus models - An intrinsic GC block drives B cell differentiation into terminally differentiated plasma cells in vitro - B cells harboring a GC block competitively contribute to the plasma cell compartment in an autoreactive setting in vivo - Lupus mice with a GC block display immune complex deposition in kidney glomeruli that is indistinguishable from their wild-type counterparts SummaryAffinity-matured autoantibodies generated in germinal centers are a hallmark of autoimmune diseases. Voss et al. block germinal centers in two autoimmune models, but surprisingly find that disease progresses unimpeded. They identify the extrafollicular pathway as a backdoor to autoimmunity.

immunology↗