RESUMO
Inflammation within the Central Nervous System (CNS) is largely controlled by the balance between CNS-specific effector and regulatory T lymphocytes. To suppress CNS-inflammation in an antigen-specific manner, CNS-specific effector and regulatory T cells thus have to be differentially regulated. We employed recombinant peptide/MHC class II tetramers to assess CNS-specific effector and regulatory T cells during the specific suppression of myelin proteolipid protein aa139-151 (PLP139-151)-induced experimental autoimmune encephalomyelitis (EAE) by intravenous injection of recombinant invariant chains (Ii) in which the CLIP region has been replaced by the PLP139-151 epitope (Ii-PLP139-151). Injection of Ii-PLP139-151 induced apoptosis in CNS-specific effector T cells. In contrast, the proportion of specific regulatory T cells was increased and these cells expressed larger amounts of molecules that mediate regulatory T cell function including transforming growth factor beta and the inducible costimulator (ICOS). Consequently, regulatory T cells from Ii-treated mice were more potent than regulatory T cells from control-treated animals in suppressing effector T cell proliferation. These data demonstrate that effector T cells and regulatory T cells directed against the same CNS-antigen can be differentially regulated in vivo to suppress CNS-autoimmunity. Recombinant Ii induce apoptosis in CNS-specific effector T cells and provoke qualitative changes in specific regulatory T cells that enhance their immunosuppressive properties.
Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Tolerância Imunológica/fisiologia , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Caspase 3/biossíntese , Caspase 3/genética , Encefalomielite Autoimune Experimental/imunologia , Citometria de Fluxo , Genes MHC da Classe II/imunologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Camundongos , Proteínas Recombinantes/química , Células Th2/imunologiaRESUMO
In addition to their immunostimulatory capacity, dendritic cells (DCs) play a crucial role in central and peripheral tolerance mechanisms. In the absence of an infection, immature DCs constantly take up, process and present self-antigens to specific T cells, which leads to the induction of T-cell anergy or deletion. In recent years, several additional mechanisms have been identified by which DCs constantly downregulate immune responses to maintain immunological tolerance. Among these are the complex interactions between several DC subtypes and different types of regulatory T cells. In this review, we summarize recent key findings and concepts in this field.
Assuntos
Autoimunidade/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-1/imunologia , Humanos , Timo/citologia , Timo/imunologiaRESUMO
The prerequisites of peripheral activation of self-specific CD4(+) T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139-151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IA(s)/PLP(139-151) tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-gamma production by self-specific CD4(+) T cells. In addition, PT promoted the generation of CD4(+)CD62L(low) effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4(+)CD62L(high) cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c(+)CD4(+) dendritic cells whereas CD11c(+)CD8alpha(+) dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4(+)CD62L(low) cells and indicate that CD4(+)CD62L(low) effector T cells and CD11c(+)CD4(+) dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.