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* Division of Dermatology, Department of Medicine, David Geffen School of Medicine,
Department of Microbiology, Immunology and Molecular Genetics, and
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;
Department of Dermatology, University of Southern California School of Medicine, Los Angeles, CA 90033; and
¶ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
The differentiation of monocytes into dendritic cells (DC) is a key mechanism by which the innate immune system instructs the adaptive T cell response. In this study, we investigated whether leukocyte Ig-like receptor A2 (LILRA2) regulates DC differentiation by using leprosy as a model. LILRA2 protein expression was increased in the lesions of the progressive, lepromatous form vs the self-limited, tuberculoid form of leprosy. Double immunolabeling revealed LILRA2 expression on CD14+, CD68+ monocytes/macrophages. Activation of LILRA2 on peripheral blood monocytes impaired GM-CSF induced differentiation into immature DC, as evidenced by reduced expression of DC markers (MHC class II, CD1b, CD40, and CD206), but not macrophage markers (CD209 and CD14). Furthermore, LILRA2 activation abrogated Ag presentation to both CD1b- and MHC class II-restricted, Mycobacterium leprae-reactive T cells derived from leprosy patients, while cytokine profiles of LILRA2-activated monocytes demonstrated an increase in TNF-
, IL-6, IL-8, IL-12, and IL-10, but little effect on TGF-β. Therefore, LILRA2 activation, by altering GM-CSF-induced monocyte differentiation into immature DC, provides a mechanism for down-regulating the ability of the innate immune system to activate the adaptive T cell response while promoting an inflammatory response.
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 National Institutes of Health Grants AR40312 and AI22553 (to R.L.M.), AR053104-01 (to D.J.L.), and AI056154 and AI069120 (to G.C.); the Dermatology Foundation (to D.J.L.); and the Lymphoma and Leukemia Society (to B.G.).
2 Address correspondence and reprint requests to Dr. Robert L. Modlin, University of California-Los Angeles, Division of Dermatology, 10833 LeConte Avenue, 52-121 Center for the Health Sciences, Los Angeles, CA 90095. E-mail address: rmodlin{at}mednet.ucla.edu
3 Abbreviations used in this paper: DC, dendritic cell; iDC, immature dendritic cell, L-lep, lepromatous leprosy; T-lep, tuberculoid leprosy; LILR, leukocyte immunoglobulin-like receptor; M., Mycobacterium.
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