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Hyporesponsiveness of Intestinal Dendritic Cells to TLR Stimulation Is Limited to TLR4¹

Vuk Cerovic^*, Christopher D. Jenkins, Andrew G. C. Barnes^*, Simon W. F. Milling^2,, G. Gordon MacPherson and Linda S. Klavinskis^3,*

^* Peter Gorer Department of Immunobiology, King’s College London, London, United Kingdom; and Sir William Dunn School of Pathology, Oxford, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Biotechnology and Biological Sciences Research Council (to L.S.K. and G.G.M.) and in facilities supported by funding from the Dunhill Medical Trust to the Peter Gorer Department of Immunobiology. V.C. was supported in part by a bursary from King’s College London.

² Current address: Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, U.K.

³ Address correspondence and reprint requests to Dr. Linda Klavinskis, Peter Gorer Department of Immunobiology, Floor 2, Borough Wing, Guys Hospital, Kings College London, London SE1 9RT, U.K. E-mail address: linda.klavinskis{at}kcl.ac.uk

⁴ Abbreviations used in this paper: IBD, inflammatory bowel disease; DC, dendritic cell; BMDC, bone marrow-derived DC; Flt3L, FMS–like tyrosine kinase 3 ligand; iLDC, intestinal lymph DC; LP, lamina propria; MLN, mesenteric lymph node; MLNX, mesenteric lymphadenectomized (rats); PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; qPCR, quantitative PCR.

⁵ The online version of this article contains supplemental material.