CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells
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CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells. / 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.
In: J AM SOC NEPHROL, Vol. 27, No. 11, 11.2016, p. 3368-3382.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells
AU - Evers, Beatrix D G
AU - Engel, Daniel R
AU - Böhner, Alexander M C
AU - Tittel, André P
AU - Krause, Torsten A
AU - Heuser, Christoph
AU - Garbi, Natalio
AU - Kastenmüller, Wolfgang
AU - Mack, Matthias
AU - Tiegs, Gisa
AU - Panzer, Ulf
AU - Boor, Peter
AU - Ludwig-Portugall, Isis
AU - Kurts, Christian
N1 - Copyright © 2016 by the American Society of Nephrology.
PY - 2016/11
Y1 - 2016/11
N2 - 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 (Tregs), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103(+) DCs and Tregs 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 Treg numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103(+) DCs and Tregs 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 Tregs, 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 Tregs and produced the chemokine CCL20, which is known to attract Tregs 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.
AB - 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 (Tregs), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103(+) DCs and Tregs 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 Treg numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103(+) DCs and Tregs 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 Tregs, 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 Tregs and produced the chemokine CCL20, which is known to attract Tregs 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.
KW - Animals
KW - Antigens, CD
KW - Dendritic Cells
KW - Glomerulonephritis
KW - Integrin alpha Chains
KW - Interleukin-10
KW - Kidney
KW - Mice
KW - Mice, Inbred C57BL
KW - T-Lymphocytes, Regulatory
KW - Journal Article
U2 - 10.1681/ASN.2015080873
DO - 10.1681/ASN.2015080873
M3 - SCORING: Journal article
C2 - 27036736
VL - 27
SP - 3368
EP - 3382
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 11
ER -