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Phenotypic and Functional Characterization of Ultraviolet Radiation-Induced Regulatory T Cells¹

Akira Maeda^*, Stefan Beissert, Thomas Schwarz^2,* and Agatha Schwarz^*

^* Department of Dermatology, University Kiel, Kiel, Germany; and Department of Dermatology, University Münster, Münster, Germany

Sensitization through UV-exposed skin induces regulatory T cells (Treg). In contrast to the classical CD4⁺CD25⁺ Treg that act contact dependent, UV-induced Treg (UV-Treg) suppress via IL-10, indicating a distinct subtype that requires further characterization. Depletion studies revealed that UV-Treg express the glucocorticoid-induced TNF family-related receptor (GITR) and the surface molecule neuropilin-1. The injection of T cells from UV-tolerized mice after depletion of UV-Treg into naive recipients enabled a contact hypersensitivity response, indicating that tolerization also induces T effector cells. Adoptive transfer experiments using IL-10-deficient mice indicated that the IL-10 required for suppression is derived from UV-Treg and not from host-derived cells. Activation of UV-Treg is Ag specific, however, once activated suppression is nonspecific (bystander suppression). Hence, speculations exist about the therapeutic potential of Treg generated in response to Ag that are not necessarily the precise Ag driving the pathogenic process. Thus, we studied the consequences of multiple injections of 2,4-dintrofluorobenzene (DNFB)-specific Treg into ears of naive mice followed by multiple DNFB challenges. DNFB-specific Treg were injected once weekly into the left ears of naive mice and DNFB challenge was performed always 24 h later. After three injections, a challenging dose of DNFB was applied on the right ear. This resulted in pronounced ear swelling, indicating that the subsequent boosting of DNFB-specific Treg had caused sensitization of the naive mice against DNFB. These data demonstrate that UV-Treg express GITR and neuropilin-1 and act via bystander suppression. However, constant boosting of Treg with Ag doses in the challenging range results in final sensitization that might limit their therapeutic potential.

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 German Research Foundation Grants SCHW 1177/1-2 and SFB 415, A16 and Deutsche Krebshilfe (107891).

² Address correspondence and reprint requests to Dr. Thomas Schwarz, Department of Dermatology, University Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany. E-mail address: tschwarz{at}dermatology.uni-kiel.de

³ Abbreviations used in this paper: CHS, contact hypersensitivity; CFDA-SE, carboxyfluorescein diacetate succinimidyl ester; DNFB, 2,4-dintrofluorobenzene; GITR, glucocorticoid-induced TNF family-related receptor; i.c., intracutaneous(ly); OXA, oxazolone; Treg, regulatory T cell; UV-Treg, UV-induced Treg.