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Direct Presentation of a Melanocyte-Associated Antigen in Peripheral Lymph Nodes Induces Cytotoxic CD8⁺ T Cells

¹ Louis Jeantet Laboratory, Skin Cancers, Department of Dermatology and ² Department of Pathology-Immunology, University Medical Center, Geneva, Switzerland and ³ Swiss Institute for Experimental Cancer Research; ⁴ Biochemistry institute, Lausanne University, Epalinges, Switzerland

Requests for reprints: Bertrand Huard, Louis Jeantet Laboratory, University Medical Center, rue Michel Servet 1, 1211 Geneva 4, Switzerland. Phone: 41-22-379-58-11; Fax: 41-22-379-58-02; E-mail: bertrand.huard{at}medecine.unige.ch.

Key Words: melanoma • T cells • Tolerance

Encounter of self-antigens in the periphery by mature T cells induces tolerance in the steady-state. Hence, it is not understood why the same peripheral antigens are also promiscuously expressed in the thymus to mediate central tolerance. Here, we analyzed CD8⁺ T-cell tolerance to such an antigen constituted by ovalbumin under the control of the tyrosinase promoter. As expected, endogenous CD8⁺ T-cell responses were altered in the periphery of transgenic mice, resulting from promiscuous expression of the self-antigen in mature medullary epithelial cells and deletion of high-affinity T cells in the thymus. In adoptive T-cell transfer experiments, we observed constitutive presentation of the self-antigen in peripheral lymph nodes. Notably, this self-antigen presentation induced persisting cytotoxic cells from high-affinity CD8⁺ T-cell precursors. Lymph node resident melanoblasts expressing tyrosinase directly presented the self-antigen to CD8⁺ T cells, independently of bone marrow–derived antigen-presenting cells. This peripheral priming was independent of the subcellular localization of the self-antigen, indicating that this mechanism may apply to other melanocyte-associated antigens. Hence, central tolerance by promiscuous expression of peripheral antigens is a mandatory, rather than a superfluous, mechanism to counteract the peripheral priming, at least for self-antigens that can be directly presented in lymph nodes. The peripheral priming by lymph node melanoblasts identified here may constitute an advantage for immunotherapies based on adoptive T-cell transfer. [Cancer Res 2008;68(20):8410–8]