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* Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
Immunological tolerance is crucial to avoid autoimmune and inflammatory diseases; however, the mechanisms involved are incompletely understood. To study peripheral tolerance to skin-associated Ags, we generated new transgenic mice expressing a membrane-bound form of OVA in skin under the human keratin 14 (K14) promoter (K14-mOVA mice). In contrast to other transgenic mice expressing similar self-Ags in skin, adoptive transfer of Ag-specific T cells does not induce inflammatory skin disease in our K14-mOVA mice. OVA-specific T cells transferred into K14-mOVA mice are activated in lymphoid tissues, undergo clonal expansion, and eventually acquire effector function. Importantly, these Ag-specific T cells selectively up-regulate expression of E-selectin ligand in cutaneous lymph nodes but not in mesenteric lymph nodes and spleen, demonstrating that expression of endogenous self-Ags in skin dictates imprinting of skin tissue homing in vivo. However, an additional inflammatory signal, here induced by tape stripping, is required in K14-mOVA mice to induce T cell migration to skin and development of inflammatory skin disease. Depletion of regulatory CD4+CD25+ T cells did not provoke homing of transferred T cells to skin under steady-state conditions, indicating that these cells are not the key regulators for inhibiting T cell homing in K14-mOVA mice. Both skin-derived and lymph node-resident CD8
+ dendritic cells are responsible for Ag presentation in vivo and induce tolerance to skin Ags, as we show by selective depletion of langerin+ and CD11c+ dendritic cells. Taken together, controlled skin homing of T cells is critical for the maintenance of peripheral immune tolerance to epidermal self-Ags.
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 research was supported by The Swiss National Science Foundation (Grant PA00A3-119493, to T.B.), the Howard Hughes Medical Institute Research Training Fellowship for medical students (to L.P.), Crohn’s and Colitis Foundation of America (to M.A.W.), the Harvard Skin Disease Research Center (to T.K.), and Netherlands Organization for Scientific Research-Veni Grant and RO1-AR052810 (to M.B.).
2 Current address: Department of Dermatology, University of California, San Francisco, CA.
3 Address correspondence and reprint requests to Dr. Marianne Boes, Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands. E-mail address: mboes{at}umcutrecht.nl
4 Abbreviations used in this paper: DC, dendritic cell; ESL, E-selectin ligand; PSL, P-selectin ligand; CLN, cutaneous lymph node; MLN, mesenteric lymph node; BM, bone marrow; Tg, transgenic; SPL, spleen; LN, lymph node; mOVA, membrane-bound OVA; DT, diphteria toxin; WT, wild type; β2m, β2-microglobulin; Treg, regulatory T cell; LC, Langerhans cell; dDC, dermal DC; EGFP, enhanced GFP; ALN, auricular LN.
5 The online version of this article contains supplemental material.
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