Fas/fas ligand pathway, apoptosis, and clonal anergy involved in systemic acetylcholine receptor T cell epitope tolerance

The cellular mechanisms of high dose systemic acetylcholine receptor (AChR) T cell epitope, α146-162 peptide-induced tolerance in experimental myasthenia gravis were examined. CD4 cells are the prime target for α146-162 peptide-induced tolerance. The expression of CD69, Fas, and B7.2 molecules on AChR-immune lymphocytes was enhanced within 4-12 h after tolerance induction. A high dose of α146-162 peptide in IFA failed to suppress T cell proliferation and/or clinical myasthenia gravis in lpr and gld mice deficient in Fas and Fas ligand, respectively. A high dose of α146-162 peptide in IFA in AChR-immunized mice induced apoptosis of BV6 cells. Further, reconstitution of IL-2 in vitro-recovered α146-162 peptide tolerized T cell proliferation, IFN-γ, and IL-10 production. The findings implicate the possible role of Fas-/Fas ligand-mediated apoptosis and the resulting clonal anergy as the mechanisms of high dose AChR α146-162 peptide-induced tolerance on CD4 cells.