Evers Beatrix D G, Engel Daniel R, Böhner Alexander M C, Tittel André P, Krause Torsten A, Heuser Christoph, Garbi Natalio, Kastenmüller Wolfgang, Mack Matthias, Tiegs Gisa, Panzer Ulf, Boor Peter, Ludwig-Portugall Isis, Kurts Christian
Institute of Experimental Immunology, University Clinic of the Rheinische Friedrich Wilhelms Universität, Bonn, Germany.
Institute for Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany.
J Am Soc Nephrol. 2016 Nov;27(11):3368-3382. doi: 10.1681/ASN.2015080873. Epub 2016 Apr 1.
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), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103 DCs and T 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 numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103 DCs and T 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 T, 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 and produced the chemokine CCL20, which is known to attract T into the kidney. Our findings show that CD103 DCs foster intrarenal FoxP3 T accumulation, thereby antagonizing proinflammatory CD11b DCs. Thus, increasing CD103 DC numbers or functionality might be advantageous in cGN.
肾树突状细胞（DCs）调节致肾炎性T细胞反应。大多数肾DCs属于CD11b亚群，并促进新月体性肾小球肾炎（cGN）。CD103亚群在肾DCs中占比不到5%，其功能尚不清楚。我们使用多种基因改造小鼠品系研究了CD103 DCs在cGN中的作用，这些品系使我们能够减少这些细胞的数量。在所有品系中，我们检测到肾内FoxP3调节性T细胞（Tregs）数量减少，而Tregs可预防cGN。缺乏转录因子Batf3的小鼠，其CD103 DCs和Tregs的减少比其他所用品系更为显著，并且cGN的恶化最为严重。在Langerin-DTR小鼠中，CD103 DCs数量条件性减少50%，使Tregs数量减半，但这并不足以显著加重cGN。缺乏细胞因子Flt3L的小鼠，其CD103 DCs和Tregs比Langerin-DTR小鼠少，但cGN比Batf3小鼠轻，这可能是因为促炎性CD11b DCs也有所减少。相反，补充Flt3L增加了CD103 DCs和Tregs的数量，但也增加了促炎性CD11b DCs的数量。在抗体介导去除CD11b DCs后，补充Flt3L可改善cGN。从机制上讲，CD103 DCs使共培养的T细胞分化为Tregs，并产生趋化因子CCL20，已知CCL20可将Tregs吸引到肾脏中。我们的研究结果表明，CD103 DCs促进肾内FoxP3 Tregs的积累，从而对抗促炎性CD11b DCs。因此，增加CD103 DCs的数量或功能可能对cGN有益。
