期刊
JOURNAL OF IMMUNOLOGY
卷 182, 期 8, 页码 4665-4674出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0803628
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- NIAMS NIH HHS [R01 AR065807, R01 AR052810-03, R01 AR052810-04, R01 AR052810, R01-AR052810, R01 AR052810-02] Funding Source: Medline
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 alpha(+) 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 Journal of Immunology, 2009, 182: 4665-4674.
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