Involvement of IFN-γ and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis

Autoaggressive, myelin-reactive T cells are involved in multiple sclerosis and its prototype experimental autoimmune encephalomyelitis (EAE) in mice. A peripheral negative feedback mechanism involving regulatory CD4+ and CD8+T cells (Treg) operates to suppress disease-mediating T cell responses. We have recently characterized a novel population of Qa-1a-restricted, TCR-peptide-reactive CD8 alpha alpha+TCR alpha beta+ Treg that induce apoptotic depletion of the encephalitogenic V beta 8.2 cells in vivo and provide protection from EAE. Here we have used mice deficient in perforin. Fas/FasL and IFN-gamma molecules to investigate their role in Treg-mediated regulation of EAE. Data show that Fas/FasL interactions are not involved, but regulation mediated by Treg is dependent on the presence of IFN-gamma and the perforin pathway. These data provide a molecular mechanism of Treg-mediated killing of the pathogenic T cells and have important implications in the design of immune interventions for demyelinating disease. (C) 2010 Elsevier B.V. All rights reserved.