Inhibitor of NF kappa B Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN

The NF kappa B transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NF kappa B inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NF kappa B-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases

CD103+Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10–Producing Regulatory T Cells

Kidney dendritic cells (DCs) regulate nephritogenic T cell responses. Most kidney DCs belong to the CD11b(+) subset and promote crescentic GN (cGN). The function of the CD103(+) subset, which represents <5% of kidney DCs, is poorly understood. We studied the role of CD103(+) DCs in cGN using several lines of genetically modified mice that allowed us to reduce the number of these cells. In all lines, we detected a reduction of FoxP3(+) intrarenal regulatory T cells (T-regs), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103(+) DCs and T-regs than did the other lines used, and showed the most profound aggravation of cGN. The conditional reduction of CD103(+) DC numbers by 50% in Langerin-DTR mice halved T-reg numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103(+) DCs and T-regs than Langerin-DTR mice but exhibited milder cGN than did Batf3(-/-) mice presumably because proinflammatory CD11b(+) DCs were somewhat depleted as well. Conversely, Flt3L supplementation increased the number of CD103(+) DCs and Treg but also of proinflammatory CD11b(+) DCs. On antibody-mediated removal of CD11b(+) DCs, Flt3L supplementation ameliorated cGN. Mechanistically, CD103(+) DCs caused cocultured T cells to differentiate into T-regs and produced the chemokine CCL20, which is known to attract T-regs into the kidney. Our findings show that CD103(+) DCs foster intrarenal FoxP3(+) Treg accumulation, thereby antagonizing proinflammatory CD11b(+) DCs. Thus, increasing CD103(+) DC numbers or functionality might be advantageous in cGN