Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent stepin ΔinvG S. Typhimurium colitis

Author:

Hapfelmeier Siegfried1,Müller Andreas J.1,Stecher Bärbel1,Kaiser Patrick1,Barthel Manja1,Endt Kathrin1,Eberhard Matthias1,Robbiani Riccardo1,Jacobi Christoph A.2,Heikenwalder Mathias3,Kirschning Carsten4,Jung Steffen5,Stallmach Thomas6,Kremer Marcus7,Hardt Wolf-Dietrich1

Affiliation:

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

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

6. Institute of Clinical Pathology, University Hospital of Zurich, CH-8091 Zürich, Switzerl

7. Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München,D-81675 München, Germany

Abstract

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 ΔinvG mutant lacking a functional type 3 secretion system-1 (ΔinvG)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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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