Hyporesponsiveness of Intestinal Dendritic Cells to TLR Stimulation Is Limited to TLR4

Abstract

Dendritic cells (DCs) are crucial to intestinal immune regulation because of their roles in inducing protective immunity against pathogens while maintaining tolerance to commensal bacteria. Nonetheless, relatively little is known about intestinal DC responsiveness to innate immune stimuli via TLRs. We have previously shown that DCs migrating from the rat intestine in lymph (iLDCs) are hyporesponsive to LPS stimulation, thus possibly preventing harmful immune responses being induced to commensal flora. In this study, to understand how iLDC function is regulated by innate immune stimuli, we have characterized the expression and function of TLRs in iLDCs isolated from the thoracic duct lymph of mesenteric lymphadenectomized rats and compared these with DCs grown from bone marrow in the presence of Flt3 ligand. We show that iLDCs express mRNAs for all TLRs, but express significantly less TLR4 mRNA than bone marrow-derived DCs. Functionally, iLDCs could be activated by TLR agonists representing intestinal pathogen-associated molecular patterns, with the important exception of the TLR4 agonist LPS. Furthermore, we show that DCs in the intestinal wall interact directly with noninvasive bacteria (Bacillus subtilis spores), leading to an increase in the output of activated iLDCs into lymph, and that DCs containing spores are activated selectively. These data highlight a functional difference between TLR4 and other TLRs. As iLDCs can respond to TLR stimulation in vitro, there must be other mechanisms that prevent their activation by commensal bacteria under steady-state conditions.

TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa

“…In the intestine, TLR5 signaling activates lamina propria DCs, which then promote Th17 differentiation (23). In contrast, intestinal DCs do not respond to TLR4 stimulation (23,46). Flagellin treatment enhanced the transcription of the genes coding for CD14, LPB, MAL, and TLR2 (Supplemental Fig.…”

Intestinal CD103+ dendritic cells: master regulators of tolerance?

“…Although CD103 + LP DCs can also cross-present exogenous antigens to T cells [36] and express high levels of CCR7 [37], the expression and function of TLR by mucosal CD103 + DCs remains an unresolved issue. Although migrating CD103 + DCs in rat intestinal lymph appear to express all TLRs except TLR4 [38], early studies of TLR expression by LP DCs in mice used heterogeneous populations of mononuclear cells, and are now difficult to interpret [39,40]. A further important difference between CD103 + DCs in the LP compared with other tissues is that the LP population is heterogeneous, and contains subsets of CD11b + CD8a -and CD11b -CD8a + DCs that are found among CD103 -DCs elsewhere [41,42].…”

Human Intestinal Lamina Propria CD1c+ Dendritic Cells Display an Activated Phenotype at Steady State and Produce IL-23 in Response to TLR7/8 Stimulation

“…+ DCs express less TLR4 but more TLR5 than PB CD1c + DCs TLR expression levels may, in part, determine the response pattern of DCs to microbial products, and low TLR expression on gut DCs was postulated to play a role in the tolerance of commensal organisms (28)(29)(30). Given that we observed blunted cytokine responses by LP CD1c + DCs to TLR4 and TLR5 stimulation, we compared the surface expression of TLR4 and TLR5 on CD1c + DCs in LP (n = 6-7) versus PB (n = 9).…”