Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis.
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 DeltainvG mutant lacking a functional type 3 secretion system-1 (DeltainvG)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.
Hapfelmeier
Siegfried
S
Institute of Microbiology, D-BIOL, ETH Zürich, CH-8093 Zürich, Switzerland.
Müller
Andreas J
AJ
Stecher
Bärbel
B
Kaiser
Patrick
P
Barthel
Manja
M
Endt
Kathrin
K
Eberhard
Matthias
M
Robbiani
Riccardo
R
Jacobi
Christoph A
CA
Heikenwalder
Mathias
M
Kirschning
Carsten
C
Jung
Steffen
S
Stallmach
Thomas
T
Kremer
Marcus
M
Hardt
Wolf-Dietrich
WD
D000818:Animals; D018845:CD11 Antigens / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D002432:Cecum / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D019707:Receptors, Chemokine / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology* / Q000473:pathology; D012486:Salmonella typhimurium
D018845:CD11 Antigens; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019707:Receptors, Chemokine