RESUMEN
Extracorporeal photochemotherapy (ECP) that takes advantage of the immunomodulatory effects of UV light has been extensively used for many years for the treatment of several T cell-mediated diseases, including graft-versus-host disease (GvHD) and systemic scleroderma. Immune mechanisms that lead to the establishment of T cell tolerance in ECP-treated patients remain poorly known. In this study, we have tested the effect of UV/psoralen-treated BM-derived dendritic cells, referred to as ECP-BMDCs on the outcome of an antigen-specific T cell-mediated reaction, that is, contact hypersensitivity (CHS), which is mediated by CD8+ effector T cells (CD8+ Teff ). The intravenous (i.v.) injection of antigen-pulsed ECP-BMDCs in recipient C57BL/6 mice induced specific CD8+ T cells endowed with immunomodulatory properties (referred to as CD8+ TECP ), which prevented the priming of CD8+ Teff and the development of CHS, independently of conventional CD4+ regulatory T cells. CD8+ TECP mediated tolerance by inhibiting the migration and functions of skin DC and subsequently the priming of CD8+ Teff . CD8+ TECP displayed none of the phenotypes of the usual CD8+ T regulatory cells described so far. Our results reveal an underestimated participation of CD8+ T cells to ECP-induced immunomodulation that could explain the therapeutic effects of ECP in T cell-mediated diseases.
Asunto(s)
Células Dendríticas/inmunología , Dermatitis por Contacto/terapia , Tolerancia Inmunológica , Inmunomodulación/efectos de la radiación , Linfocitos T Citotóxicos/efectos de la radiación , Linfocitos T Reguladores/efectos de la radiación , Alérgenos/administración & dosificación , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células Dendríticas/citología , Células Dendríticas/trasplante , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/fisiopatología , Dinitrofluorobenceno/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Ficusina/administración & dosificación , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Fotoféresis/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Rayos UltravioletaRESUMEN
The role of T cells in contact hypersensitivity (CHS) to haptens has been well described. However, recent reports demonstrated that CHS-like reactions to experimental haptens could be induced in mice deficient in T cells and B cells, as a result of adaptive-like features of NK cells. Here, we compared hapten-specific inflammatory reactions induced by memory T cells or NK cells. Classical CHS protocols were applied to WT or T- and B-cell deficient mice. Adoptive transfers of hapten-specific T cells and NK cells were also performed. Liver NK cells from hapten-primed mice induced specific recall responses to haptens upon transfer in CD3ε-deficient mice, thus confirming the existence of "memory" NK cells in the liver. We investigated the nature of the inflammation generated in these transfer conditions and found that hapten-induced skin inflammation mediated by CD8(+) T cells or "memory" NK cells are different. Indeed, ear swelling induced by memory NK cells was transient and not associated with cellular infiltrate and inflammation markers, characteristic for T-cell-mediated responses. Thus, NK cells and T cells mediate distinct forms of skin inflammation. NK cell-mediated pathogenesis does not rely on cellular infiltrate and could be involved in atypical forms of adverse drug reactions.