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

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.

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

“…MyD88-deficient mice are more susceptible to several intestinal bacteria and pathogens such as Listeria monocytogenes (25), vancomycinresistant Enterococcus (22), Salmonella typhimurium (26,27), and Citrobacter rodentium (28). Also, it has been shown by several groups that MyD88 signaling is protective in a model of acute induced colitis (5,6,29).…”

Visualizing dendritic cell migration within the skin

“…DCs in these mice exhibit high Xuorescence, and are readily identiWable by both Xuorescence microscopy and Xow cytometry. These mice have not only greatly improved our understanding of the behavior of endogenous DCs in the LN (Lindquist et al 2004;Shakhar et al 2005), but also their roles in various models of infection (Aoshi et al 2008;Hapfelmeier et al 2008;Veres et al 2007). They also enabled the visualization of intestinal DCs (Flores-Langarica et al 2005) and the identiWcation of a previously uncharacterized population of DCs in the brain (Bulloch et al 2008).…”

Probing in vivo dendritic cell functions by conditional cell ablation

“…Viruses cDC requirement for LCMV, 35 HSV-1, 36 VSV, 37 influenza, 38 CTL response cDC independence of anti-VSV B and CD4 T-cell response 36,39 Bacteria cDC requirement for anti-Listeria CTL response 11,40 cDC requirement for efficient Mycobacterium tuberculosis CD4 T-cell response 41 cDC requirement for anti-Salmonella response 42,43 cDC independence of UPEC clearance 44 Parasites cDC requirement for anti-Plasmodium 11 and anti-Leishmania response 45,46 Prions cDC requirement for intestinal Scrapie agent neuroinvasion 47 Miscellaneous Tolerance cDC role in Ig complex-mediated priming and tolerization 48,49 cDC independence of peripheral CD4 T-cell tolerization 50 NK responses cDC requirement for NK cell activation by IL-15 trans-presentation 25 NKT responses cDC requirement for glycolipid presentation 51,52 CTL responses cDC requirement for efficient CTL memory generation 27 Respiratory tract cDC requirement for asthma and experimental allergic rhinitis 18,53 Tumor studies cDC requirement for antitumor immunity 52 DC functions by conditional cell ablation A Sapoznikov and S Jung subpopulations and generally provided by non-hematopoietic cells, including stromal and follicular dendritic cells; 58 and (2) the chemokine macrophage migration inhibitory factor (MIF) that controls mature B-and tumor cell survival through triggering of the CD74-CD44 receptor complex. [59][60][61] 70 on pDC.…”