RESUMO
Tregs represent an interesting therapeutic tool to modulate immune responses that could be deleterious in autoimmune diseases and in transplantation. However, phenotype and functions of Tregs do not seem to be stable, and recent data suggest that FoxP3-expressing Tregs can be driven to produce IL-17. In this study, we have analyzed the role of pDCs versus cDCs on Treg responses and underlined that pDCs have an intrinsic, unique capacity to induce IL-17 secretion from T cells. We showed in rats that FoxP3(+) Tregs were able to secrete IL-17 only when stimulated by allogeneic, mature pDCs but not cDCs. In addition, in rats and mice, mature pDCs but not cDCs inhibited in vitro Treg-suppressive functions and in the presence of Tregs, supported Th17 differentiation from naive T cells through secretion of high amounts of IL-6. These data suggest an important role for pDCs in modulating or switching Treg function and allowing Th17 differentiation.
Assuntos
Células Dendríticas/imunologia , Interleucina-17/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Ratos , Ratos Endogâmicos Lew , Linfócitos T/metabolismoRESUMO
Despite accumulating evidence for the importance of allospecific CD8(+) regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8(+) Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8(+) Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8(+) Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8(+) Tregs to suppress CD4(+) effector cells responses to first-donor Ags in vitro. When tolerogenic CD8(+) Tregs were not in contact with CD4(+) effector cells, suppression was mediated by IDO. Contact with CD4(+) effector cells resulted in alternative suppressive mechanisms implicating IFN-gamma and fibroleukin-2. In vivo, both IDO and IFN-gamma were involved in tolerance induction, suggesting that contact with CD4(+) effector cells is crucial to modulate CD8(+) Tregs function in vivo. In conclusion, CD8(+) Tregs and pDCs interactions were necessary for suppression of CD4(+) T cells and involved different mechanisms modulated by the presence of cell contact between CD8(+) Tregs, pDCs, and CD4(+) effector cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Coração/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Adenoviridae/genética , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Proliferação de Células , Células Dendríticas/citologia , Células Dendríticas/imunologia , Citometria de Fluxo , Vetores Genéticos/genética , Transplante de Coração/métodos , Masculino , Modelos Animais , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/citologia , Transdução Genética , Transplante HomólogoRESUMO
The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.
Assuntos
Terapia de Imunossupressão/métodos , Transplante de Fígado/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Transplante de Órgãos/métodos , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Doadores VivosRESUMO
Mesenchymal stem cells (MSCs) display immunomodulatory properties mediated by various factors, including inducible nitric oxide synthase (iNOS). Since heme oxygenase-1 (HO-1) is a potent immunosuppressive enzyme, we tested the hypothesis that HO-1 could mediate the immunosuppressive effects of MSCs. We generated adult rat MSCs that inhibited T-cell proliferation in vitro. These MSCs expressed both HO-1 and iNOS. In vitro, whereas neither HO-1 nor iNOS inhibition alone could interfere with the immunosuppressive properties of rat MSCs, simultaneous inhibition of both enzymes restored T-cell proliferation. In vivo, injection of MSCs significantly delayed heart allograft rejection, and inhibition of either HO-1 or iNOS totally reversed the protective activity of MSCs, inducing rejection. Adult human MSCs also expressed HO-1; in these cells, HO-1 inhibition was sufficient to completely block their immunosuppressive capacity. In conclusion, we show, for the first time, that HO-1 mediates the immunosuppressive properties of rat and human MSCs.