Tregs are important mediators of immune tolerance to
self antigens, and it has been suggested that Treg inactivation may cause
autoimmune disease. Therefore,
immunotherapy approaches that aim to restore or expand
autoantigen-specific Treg activity might be beneficial for the treatment of
autoimmune disease. Here we report that Treg-mediated suppression of
autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural
autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune
neuroinflammation in a mouse model of
multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after
antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by
TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that
autoantigen expression in the liver may generate
autoantigen-specific Tregs. Thus, targeting of
autoantigens to hepatocytes may be a novel approach to prevention or treatment of
autoimmune diseases.