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Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5

Abstract

The intestinal cell types responsible for defense against pathogenic organisms remain incompletely characterized. Here we identify a subset of CD11chiCD11bhi lamina propria dendritic cells (LPDCs) that expressed Toll-like receptor 5 (TLR5) in the small intestine. When stimulated by the TLR5 ligand flagellin, TLR5+ LPDCs induced the differentiation of naive B cells into immunoglobulin A–producing plasma cells by a mechanism independent of gut-associated lymphoid tissue. In addition, by a mechanism dependent on TLR5 stimulation, these LPDCs promoted the differentiation of antigen-specific interleukin 17–producing T helper cells and type 1 T helper cells. Unlike spleen DCs, the LPDCs specifically produced retinoic acid, which, in a dose-dependent way, supported the generation and retention of immunoglobulin A–producing cells in the lamina propria and positively regulated the differentiation interleukin 17–producing T helper cells. Our findings demonstrate unique properties of LPDCs and the importance of TLR5 for adaptive immunity in the intestine.

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Figure 1: Four subsets of CD11c+ LPCs in the small intestine.
Figure 2: CD11chiCD11bhi LPDCs specifically express TLR5.
Figure 3: CD11chiCD11bhi LPDCs induce IgA+ plasma cell differentiation.
Figure 4: Function of retinoic acid released by CD11chiCD11bhi LPDCs in IgA synthesis.
Figure 5: TLR5-dependent TH-17 cell differentiation by CD11chiCD11bhi LPDCs.
Figure 6: TLRs are essential for CD11chiCD11bhi LPDC–mediated immune responses.

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Acknowledgements

We thank N. Kitagaki for technical assistance; T. Kawai and C. Coban for discussions; and A. Shigeta and M. Matsumoto for the distribution of OT-II-transgenic mice. Il6−/− mice (C57BL/6) were provided by M. Kopf (Swiss Federal Institute of Technology), and OT-II transgenic mice (C57BL/6) were provided by W.R. Heath (The Walter and Eliza Hall Institute of Medical Research). Supported by the Ministry of Education, Culture, Sports, Science and Technology in Japan (S.A.), the Ministry of Health, Labour and Welfare in Japan (S.A.), the 21st Century Center of Excellence Program of Japan (S.A.), the World Premier International Research Center (S.A.) and the National Institutes of Health (AI070167 to S.A.).

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K.F. and S.U. did most of the experiments; S.U., K.J.I. and M.H.J. designed all the experiments; B.-G.Y. helped with the immunohistochemical analysis; Y.-J.J. and M.N. helped to isolate cells; S.S., T.T. and M.Y. provided advice for the experiments; Y.Y. provided Id2−/− mice; H.K. and M.M. provided advice for the experiments and manuscript; S.U. and S.A. prepared the manuscript; and S.A. directed the research.

Corresponding author

Correspondence to Shizuo Akira.

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Uematsu, S., Fujimoto, K., Jang, M. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 9, 769–776 (2008). https://doi.org/10.1038/ni.1622

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