The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20070633
The Journal of Experimental Medicine, Vol. 205, No. 2, 437-450
The Rockefeller University Press, 0022-1007 $30.00
© Hapfelmeier et al.
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ARTICLE

 Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent stepin {Delta}invG S. Typhimurium colitis

Siegfried Hapfelmeier1, Andreas J. Müller1, Bärbel Stecher1, Patrick Kaiser1, Manja Barthel1, Kathrin Endt1, Matthias Eberhard1, Riccardo Robbiani1, Christoph A. Jacobi2, Mathias Heikenwalder3, Carsten Kirschning4, Steffen Jung5, Thomas Stallmach6, Marcus Kremer7, and Wolf-Dietrich Hardt1

1 Institute of Microbiology, D-BIOL, ETH Zürich, CH-8093 Zürich, Switzerland
2 Universitätsklinikum Tübingen, Medizinische Klinik I, 72076 Tübingen, Germany
3 Institute of Neuropathology and 6 Institute of Clinical Pathology, University Hospital of Zurich, CH-8091 Zürich, Switzerland
4 Institut für Mikrobiologie, Immunologie und Hygiene, Technische Universität München, D-81675 München, Germany
5 Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel
7 Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München,D-81675 München, Germany

CORRESPONDENCE Wolf-Dietrich Hardt: hardt{at}micro.biol.ethz.ch

Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 {Delta}invG mutant lacking a functional type 3 secretion system-1 ({Delta}invG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c+CX3CR1+ mucosal DCs. At later stages, the bacteria became associated with other (CD11c–CX3CR1–) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.

Abbreviations used: {Delta}invG, S. Typhimurium SL1344 {Delta}invG mutant lacking a functional TTSS-1; DTX, diphtheria toxin; DTR, DTX receptor; EGFP, enhanced GFP; HE, hematoxylin and eosin; MAMP, microbe associated molecular pattern; mLN, mesenteric lymph node; PP, Peyer's patch; SPF, specific pathogen–free; S. Typhimurium, Salmonella enterica subspecies 1 serovar Typhimurium; TLR, Toll-like receptor; TTSS-1, type 3 secretion system-1; TTSS-2, type 3 secretion system-2.

S. Hapfelmeier and A.J. Müller contributed equally to this paper.


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