Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens

Ansuman T. Satpathy, Carlos G. Briseño, Jacob S. Lee, Dennis Ng, Nicholas A. Manieri, Wumesh Kc, Xiaodi Wu, Stephanie R. Thomas, Wan Ling Lee, Mustafa Turkoz, Keely G. McDonald, Matthew M. Meredith, Christina Song, Cynthia J. Guidos, Rodney D. Newberry, Wenjun Ouyang, Theresa L. Murphy, Thaddeus S. Stappenbeck, Jennifer L. Gommerman, Michel C. NussenzweigMarco Colonna, Raphael Kopan, Kenneth M. Murphy

Research output: Contribution to journalArticlepeer-review

245 Scopus citations

Abstract

Defense against attaching-and-effacing bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. Although CD4+ and NKp46+ innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete mice of specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the attaching-and-effacing pathogen Citrobacter rodentium. We found that the signaling receptor Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b+ cDCs were an obligate source of IL-23 required for survival after infection with C. rodentium, but CD103 + cDCs dependent on the transcription factor Batf3 were not. Our results demonstrate a nonredundant function for CD11b+ cDCs in the response to pathogens in vivo.

Original languageEnglish (US)
Pages (from-to)937-948
Number of pages12
JournalNature immunology
Volume14
Issue number9
DOIs
StatePublished - Sep 2013

Bibliographical note

Funding Information:
We thank B. Sleckman (Washington University in St. Louis) for Nik−/− mice; T. Watts (University of Toronto) for Ifnar1−/− mice; J. Boothroyd (Stanford University) for the plasmid PRU-FLuc-GFP; the Immunological Genome Project consortium for use of their database54; and the Alvin J. Siteman Cancer Center at Washington University School of Medicine for use of the Center for Biomedical Informatics and Multiplex Gene Analysis Genechip Core Facility. Supported by the Howard Hughes Medical Institute, the US National Institutes of Health (AI076427-02 to K.M.M., R01 GM55479 to R.K., R01 DE021255-01 and U01 AI095542-01 to M.C., R01 DK071619 to T.S.S. and R01 DK064798 to R.D.N.), the US Department of Defense (W81XWH-09-1-0185 to K.M.M.), the American Heart Association (12PRE8610005 to A.T.S. and 12PRE12050419 to W.K.), the Canadian Institutes of Health Research (MOP 67157 to J.L.G. and FRN 11530 to C.J.G.) and the National Cancer Institute (P30 CA91842 for the Alvin J. Siteman Cancer Center).

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