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Lipopolysaccharide-Activated IL-10-Secreting Dendritic Cells Suppress Experimental Autoimmune Uveoretinitis by MHCII-Dependent Activation of CD62L-Expressing Regulatory T Cells¹

Annie W. T. Lau^*, Sabine Biester^*, Richard J. Cornall and John V. Forrester^*,2

^* Department of Ophthalmology, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom; and Nuffield Department of Clinical Medicine, Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic, although there is accumulating evidence that they can also be tolerogenic and induce Ag-specific regulatory T cells (Tregs). However, the mechanism of this Treg induction and the site of Treg action in vivo are yet to be defined. In this study, using the experimental model of interphotoreceptor retinoid-binding protein peptide (1–20)-induced experimental autoimmune uveoretinitis, we show that s.c. inoculation of IRBP-peptide-pulsed IL-10-producing LPS-activated mature DC (IL-10-DC) at one site (the cervical region) suppresses autoimmunity induced at a separate site (the inguinal region). Our data show that s.c. IL-10-DC correlates with an increase in the number of CD4⁺CD25⁺Foxp3⁺ Tregs at the DC-draining lymph nodes (DC-dLN). However, although MHCII^–/– IL-10-DC also induces Treg expansion at this DC-dLN, they failed to suppress experimental autoimmune uveoretinitis. Furthermore, unlike wild-type IL-10-DC, MHCII^–/– IL-10-DC did not correlate with an increase in the percentage of Tregs expressing CD62L at the DC-dLN, nor did they associate with an increase in Treg number at a distal site. Similar effects were also observed after s.c. hen egg lysozyme-pulsed IL-10-DC, which produced a strong reduction in the number and activation of proliferating Ag-specific CD4⁺ 3A9 T effector cells. We therefore propose that IL-10-DC require MHCII-dependent Ag presentation, and hence TCR ligation, to promote CD62L-mediated trafficking of Tregs to the site of T effector cell priming, where they suppress autoimmunity.

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 project was supported by the Development Trust (University of Aberdeen) and the National Health Service Grampian Endowment Trust (07/49).

² Address correspondence and reprint requests to John V. Forrester, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, U.K. E-mail address: j.forrester{at}abdn.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; dLN, draining lymph node; EAU, experimental autoimmune uveoretinitis; HEL, hen egg lysozyme; IRBP, interphotoreceptor retinoid-binding protein; LN, lymph node; Teff, T effector cell; tg, transgenic; WT, wild type.