Cd137 Signaling In Regulatory Dendritic Cells Is Required For Suppressing A Systemic Inflammation In The Bm12-Inducible Model Of Systemic Lupus Erythematosus.

Abstract Background and Aims Although CD137 is well known as a costimulatory receptor in T cells, limited information is available for its immunoregulatory function. Here, we report that CD137 signaling maintains CD11b+ regulatory dendritic cells (DCs) that can suppress activation of donor TH1 and TH17 CD4+ T cells in chronic graft-versus-host disease (GVHD). Method Chronic GVHD can be induced by mouse BMT models in which donor and recipient strain combination is MHC class I identical but MHC II mismatched. This chronic GVHD model recapitulates human SLE. Results : The deletion of CD137 in recipient mice shifted the disease phenotype toward acute GVHD, which was caused by the activation of donor T cells. CD137-/- recipients had had characteristic changes associated with acute GVHD: 1) there were defects in differentiation of T follicular helper (TFH) cells, germinal-center B cells, and plasma cells, and production of anti-DNA IgG1 autoantibody; 2) their splenic DCs showed dysregulated expression of DC-specific transcription factors and pro-inflammatory genes, and 3) there were strong activation of donor T cells but decreased Treg cells in the CD137-/- recipient spleen. CD11b+ splenic DCs stimulated with agnostic anti-CD137 antibody and CpG markedly increased expression of immunomodulatory genes, and such regulatory DCs inhibited acute GVHD in CD137-/- recipients. Their suppressive action was mediated through IL-10 that is indispensable for the induction and expansion of peripheral Treg cells. Conclusion Our study identifies CD137 signaling in DCs as an important braking point to prevent systemic inflammation, and this control system may be considered as a therapeutic strategy for a variety of inflammatory and autoimmune diseases.