Abstract
The default response of the intestinal immune system to most antigens is the induction of immunological tolerance, which is difficult to reconcile with the constant exposure to ligands for TLR and other pattern recognition receptors. We showed previously that dendritic cells (DC) from the lamina propria of normal mouse intestine may be inherently tolerogenic and here we have explored how this might relate to the expression and function of Toll-like receptors (TLR). Lamina propria (LP) DC showed higher levels of TLR 2, 3, 4 and 9 protein expression than spleen and MLN DC, with most TLR-expressing DC in the gut being CD11clo, class II MHClo, CD103–, CD11b– and F4/80–. TLR expression by lamina propria DC was low in the upper small intestine and higher in distal small intestine and colon. Freshly isolated lamina propria DC expressed some CD40, CD80, CD86 and functional CCR7. These were up-regulated on CD11clo, but not on CD11chi LP DC by stimulation via TLR. However, there was little induction of IL-12 by either subset in response to TLR ligation. This was associated with constitutive IL-10 production and was reversed by blocking IL-10 function. Thus, IL-10 may maintain LP DC in a partially unresponsive state to TLR ligation, allowing them to have a critical role in immune homeostasis in the gut.
Highlights
The intestine has a vast surface area, which is exposed continuously to dietary antigens and commensal micro-organisms, as well as an array of different pathogens
A similar pattern was found in spleen dendritic cells (DC), indicating that both peripheral and mucosal DC are capable of synthesising all Toll-like receptors (TLR)
TLR 9 is characteristically expressed by plasmacytoid DC [11] and we found previously that a substantial minority of DC in lamina propria (LP) expressed B220, which is present on pDC [3]
Summary
The intestine has a vast surface area, which is exposed continuously to dietary antigens and commensal micro-organisms, as well as an array of different pathogens. We found that purified LP DC could upregulate expression of class II MHC and costimulatory molecules in response to the TLR 4 ligand LPS, but failed to synthesise IL-12p40 mRNA after this stimulation [3].
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