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 CD8αα+TCRαβ+ Treg that induce apoptotic depletion of the encephalitogenic Vβ8.2 cells in vivo and provide protection from EAE. Here we have used mice deficient in perforin, Fas/FasL and IFN-γ 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-γ 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.
Beeston
Tara
T
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Smith
Trevor R F
TR
Maricic
Igor
I
Tang
Xiaolei
X
Kumar
Vipin
V
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D054353:Perforin / Q000172:deficiency / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology
D015704:CD4 Antigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin; D007371:Interferon-gamma