RESUMO
Multiple sclerosis (MS) is often characterized by several relapses and remissions during long-term disease, but neither the responsible cells nor the mechanisms are known to date. Using an animal model of multiple sclerosis, relapsing experimental autoimmune encephalomyelitis (R-EAE) CD4+CD25+ Treg cells expressing Foxp3 and CTLA-4 intracellularly and T lymphocytes expressing surface CTLA-4 were identified in the CNS. The first remission occurred even after depletion of Treg cells, but secondary remissions from EAE were ablated. Despite the unaltered first remission autoantigen rechallenge revealed already an amplified cytokine response during acute phase. These results indicate that the cellular composition during first attack of MS predicts long-term disease progression.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Receptores de Interleucina-2/metabolismo , Linfócitos T Reguladores/fisiologia , Animais , Anticorpos/efeitos adversos , Antígenos CD , Antígenos de Diferenciação/metabolismo , Encéfalo/citologia , Antígenos CD4/metabolismo , Antígeno CTLA-4 , Células Cultivadas , Distribuição de Qui-Quadrado , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/etiologia , Feminino , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/metabolismo , Imunização/métodos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-2/imunologia , Recidiva , Indução de Remissão , Índice de Gravidade de Doença , Baço/citologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Survival of antigen-experienced T cells is essential for the generation of adaptive immune responses. Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in a completely Fas/Fas ligand (FasL)-dependent manner. CD152 cross-linking together with stimulation of CD3 and CD28 on activated Th2 cells prevented activation-induced cell death (AICD) as a result of reduced Fas and FasL expression. Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1. We show that signals induced by CD152 act directly on activated T lymphocytes and, due to its differential surface expression on activated Th1 and Th2 cells, induce resistance to AICD mainly in Th2 cells.
