RESUMO
BACKGROUND: CD4(+)CD25(+) regulatory T (Treg) cells are involved in the downmodulation of numerous immune responses to pathogens, tumors, or allergens. OBJECTIVE: In this study, we further characterized the nature of Treg cells that control skin inflammatory reactions to haptens. METHODS: In a model of contact hypersensitivity to 2,4-dinitro-fluorobenzene, we have investigated the phenotype, the specificity, and the origin of Treg cells that modulate the priming of effector CD8(+) T cells responsible for the development of the pathology. RESULTS: 2,4-Dinitrofluorobenzene immunization induced a population of CD4(+)CD25(+) Treg cells that controlled CD8(+) T-cell effector responses in a hapten-specific manner in vivo. High levels of inducible costimulator (ICOS) expression defined a population of CD4(+)CD25(+)FoxP3(+) (forkhead box protein 3) Treg cells that presented superior suppressive activity. Importantly, ICOS(+) Treg cells were distinguishable from all other FoxP3(+) Treg cells by the expression of IL-10, IL-17, and IFN-gamma. Hapten-specific Treg cells proliferating in response to their cognate antigen in vivo predominantly displayed a CD25(+)FoxP3(+)ICOS(+) phenotype. By using reporter mice, we showed that ICOS(+) Treg cells derived from the expansion of natural CD4(+)FoxP3(+) Treg cells rather than generation of adaptive Treg cells. Furthermore, the generation of ICOS(+) Treg cells depended on innate cells rather than the effector CD8(+) T-cell population. CONCLUSION: Taken together, our data show that a population of CD4(+)CD25(+)FoxP3(+) T cells upregulates ICOS on in vivo sensitization and specifically suppresses hapten-reactive CD8(+) T cells both in vivo and in vitro.
Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Dermatite Alérgica de Contato/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Regulação para Cima/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/biossíntese , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/imunologia , Dermatite Alérgica de Contato/metabolismo , Dinitrofluorbenzeno/efeitos adversos , Dinitrofluorbenzeno/farmacologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Haptenos/efeitos adversos , Haptenos/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis , Camundongos , Linfócitos T Reguladores/metabolismo , Células Th1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Irritant contact dermatitis (ICD) is a frequent inflammatory skin disease induced by skin contact with low molecular weight chemicals such as haptens endowed with proinflammatory properties. Allergic contact dermatitis (ACD) is a frequent complication of ICD and is mediated by hapten-specific T cells primed in lymph nodes by skin emigrating dendritic cells. The aim of this study was to analyze the relationship between ICD and ACD to 2,4-dinitrofluorobenezene (DNFB) in C57BL/6 and BALB/C mice, which develop a severe and a moderate skin inflammation, respectively. Upon a single skin painting with DNFB, C57BL/6 developed within hours a more severe dose-dependent ICD response as compared to BALB/C mice, which was associated with enhanced upregulation of IL-1beta, IL-6, and IL-10. Skin exposure to a low dose of DNFB resulted, in both strains, in a low ICD that resolved in a few hours. Alternatively, skin painting with either an intermediate or a high DNFB concentration induced an ICD that subsequently gave rise to an ACD reaction whose intensity was proportional to the magnitude of the ICD response and was more severe in C57BL/6 mice than in BALB/C mice. In conclusion, the hapten-induced skin contact irritation conditions the development and the severity of ACD.
Assuntos
Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/imunologia , Índice de Gravidade de Doença , Animais , Dinitrofluorbenzeno/imunologia , Dinitrofluorbenzeno/farmacologia , Relação Dose-Resposta Imunológica , Feminino , Haptenos/imunologia , Interleucina-10/genética , Interleucina-1beta/genética , Interleucina-6/genética , Irritantes/imunologia , Irritantes/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Especificidade da Espécie , Linfócitos T/imunologiaRESUMO
Contact hypersensitivity is one of the most common skin diseases and its pharmacological control is an important clinical issue. We investigated the control of contact hypersensitivity by immunosuppressive drugs administered during sensitization or challenge. Mycophenolate mofetil, methotrexate and 5-fluorouracil completely inhibited contact hypersensitivity when administered during sensitization whereas they did not decrease inflammatory reaction when administered during challenge. Conversely, mitoxantrone, and cyclophosphamide, given as a single injection at the time of sensitization or challenge, completely inhibited the reaction, a property associated with T and B cell depletion. The data indicate that antimetabolites which are cell cycle dependent inhibit clonal expansion and subsequent differentiation of cytotoxic CD8+ T cells. Their lack of effect at the time of challenge indicates that T cell proliferation is not required for the expression of effector or regulatory T cell activation. Conversely lymphoablative drugs can inactivate or destroy differentiated cytotoxic T cells with rapid kinetics.