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Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
In vitro the mannose receptor (MR) mediates Ag internalization by dendritic cells (DC) and favors the presentation of mannosylated ligands to T cells. However, in vivo MR seems to play a role not in Ag presentation but in the homeostatic clearance of endogenous ligands, which could have the secondary benefit of reducing the levels of endogenous Ag available for presentation to the adaptive immune system. We have now observed that while MR+ cells are consistently absent from T cell areas of spleen and mesenteric lymph nodes (LN), peripheral LN of untreated adult mice contain a minor population of MR+MHCII+ in the paracortex. This novel MR+ cell population can be readily identified by flow cytometry and express markers characteristic of DC. Furthermore, these MR+ DC-like cells located in T cell areas can be targeted with MR ligands (anti-MR mAb). Numbers of MR+MHCII+ cells in the paracortex are increased upon stimulation of the innate immune system and, accordingly, the amount of anti-MR mAb reaching MR+MHCII+ cells in T cell areas is dramatically enhanced under these conditions. Our results indicate that the MR can act as an Ag-acquisition system in a DC subpopulation restricted to lymphoid organs draining the periphery. Moreover, the effect of TLR agonists on the numbers of these MR+ DC suggests that the immunogenicity of MR ligands could be under the control of innate stimulation. In accordance with these observations, ligands highly specific for the MR elicit enhanced humoral responses in vivo only when administered in combination with endotoxin.
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 funded by the Arthritis Research Campaign, the Medical Research Council (U.K.), the Edward P. Abraham Research Fund, and the University of Nottingham.
2 Current address: Department of Medicine and Therapeutics, Institute of Medical Sciences University of Aberdeen, Foresterhill, Aberdeen, Scotland AB25 2ZD, U.K.
3 Current address: Centre for Clinical Immunology and Biomedical Statistics and Murdoch University, Department of Clinical Immunology, Level 2, North Block, Royal Perth Hospital, Wellington Street, Perth 6001, Australia.
4 Current address: Department of Clinical Medicine, Trinity Centre for Health Sciences, St. James Hospital, Dublin 8, Ireland.
5 Address correspondence and reprint requests to Dr. Siamon Gordon, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, U.K.; E-mail address: christine.holt{at}path.ox.ac.uk or Dr. Luisa Martinez-Pomares at the current address: Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham, Queen’s Medical Centre, Floor A, West Block NG7 2UH, U.K.; E-mail address: luisa.martinez-pomares{at}nottingham.ac.uk
6 Abbreviations used in this paper: DC, dendritic cell; AP, alkaline phosphatase; CR cysteine-rich; LN, lymph node; M
, macrophage; mLN, mesenteric LN; moDC, monocyte-derived DC; MR, mannose receptor; Pam3Cys4, (S)-]2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4-OH,3HCl; pLN, peripheral LN; poly(I:C), polyinosinic-polycytidylic acid; WT, wild type.
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