Phenotypic and functional characterization of ultraviolet radiation-induced regulatory T cells.
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.
Maeda
Akira
A
Department of Dermatology, University Kiel, Kiel, Germany.
Beissert
Stefan
S
Schwarz
Thomas
T
Schwarz
Agatha
A
D000818:Animals; D003877:Dermatitis, Contact / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000276:immunology / Q000528:radiation effects; D004431:Ear, External / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007108:Immune Tolerance / Q000528:radiation effects; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology / Q000528:radiation effects; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039921:Neuropilins / Q000096:biosynthesis / Q000528:radiation effects; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000528:radiation effects; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays
D018984:Epitopes, T-Lymphocyte; D053450:Glucocorticoid-Induced TNFR-Related Protein; D039921:Neuropilins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D016753:Interleukin-10; D004139:Dinitrofluorobenzene