WDFY1-expressing follicular dendritic cells play a critical role in lupus development in cGVHD mouse model

Follicular dendritic cells (FDCs) retain Ag-containing immune complexes (ICs), facilitate the selection of high-affinity antibodies, and protect B cells in germinal centers (GCs) from apoptosis. In systemic lupus erythematosus patients, apoptotic debris is found on the surface of FDCs. However, the mechanisms by which FDCs engage the protected autoreactive B cells remain unclear. WD repeat and FYVE domain-containing protein 1 (WDFY1) is an adaptor protein involved in endocytic/vacuolar membrane trafficking. We found that FDCs express a high level of WDFY1, which is required for their IC presentation. C57BL/6 mice deficient in WDFY1 generated significantly lesser titers of anti-dsDNA and anti-chromatin autoantibodies (autoAbs) than WDFY1-sufficient mice receiving an equal amount of CD4+ T cells from bm12 mice in the mouse model of inducible lupus. Decreased autoAb production in WDFY1-deficient mice correlates with less GC formation and fewer T and GC B cells in the follicle. Interestingly, T cells from WDFY1-KO mice remain capable of inducing comparable chronic graft-versus-host disease (cGVHD) in host bm12 mice as the T cells from WT mice. B cells from WDFY1-KO mice also remain capable of being fully activated and differentiated in response to independent Ag challenges. Immunofluorescence staining reveals reduced binding of ICs with FDCs in WDFY1-KO mice compared to WT control mice. Mixed leukocyte reaction results show no intrinsic defect in B cells. B-cell reconstitution in Rag1-KO mice also revealed that WDFY1 is critical for FDCs. Collectively, our studies indicate that WDFY1 knockout impairs the normal functioning of FDCs, resulting in reduced autoAb response to cGVHD.