Foxp3 + regulatory T cells are well-known immune suppressor cells in various settings. In this study, we provide evidence that knockout of the relB gene in dendritic cells (DCs) of C57BL/6 mice results in a spontaneous and systemic accumulation of Foxp3 + T regulatory T cells (Tregs) partially at the expense of microbiota-reactive Tregs. Deletion of nfkb2 does not fully recapitulate this phenotype, indicating that alternative NF-kB activation via the RelB/p52 complex is not solely responsible for Treg accumulation. Deletion of RelB in DCs further results in an impaired oral tolerance induction and a marked type 2 immune bias among accumulated Foxp3 + Tregs reminiscent of a tissue Treg signature. Tissue Tregs were fully functional, expanded independently of IL-33, and led to an almost complete Treg-dependent protection from experimental autoimmune encephalomyelitis. Thus, we provide clear evidence that RelB-dependent pathways regulate the capacity of DCs to quantitatively and qualitatively impact on Treg biology and constitute an attractive target for treatment of autoimmune diseases but may come at risk for reduced immune tolerance in the intestinal tract.
the ERC (CoG 647215). C.S. performed most experiments, analyzed data, and interpreted results; L.G.P. and S.H. performed Citrobacter rodentium infection experiments and analyzed data; M.K. and D.M. analyzed histologic data; M.P. and C.O. performed and analyzed some lamina propria stainings; A.K. designed experiments and interpreted results; and T.K. conceived and initiated the study, interpreted results, and wrote the paper.
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