Inactivation o f T Cell Receptor Peptide - specific CD 4 Regulatory T Cells Induces Chronic

T cell receptor (TCR)-recognizing regulatory cells, induced after vaccination with self-reactive T cells or TC1K peptides, have been shown to prevent autoimmunity. We have asked whether this regulation is involved in the maintenance o f peripheral tolerance to myelin basic protein (MBP) in an autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). Antigen-induced EAE in (SJL X B10.PL)F1 mice is transient in that most animals recover permanently from the disease. Most o f the initial encephalitogenic T cells recognize MBP Ac l -9 and predominantly use the T C R V[38.2 gene segment. In mice recovering from MBP-induced EAE, regulatory CD4 + T cells (Treg) specific for a single immunodominant T C R peptide B5 (76-101) from framework region 3 o f the V[38.2 chain, become primed. We have earlier shown that cloned B5-reactive Treg can specifically downregulate responses to Ac l -9 and also protect mice from EAE. These CD4 Treg clones predominantly use the TCtL V[314 or VI33 gene segments. Here we have directly tested whether deletion/blocking of the Treg from the peripheral repertoire affects the spontaneous recovery from EAE. Treatment o f F1 mice with appropriate V[3-specific monoclonal antibodies resulted in an increase in the severity and duration o f the disease: even relapses were seen in one-third to one-half o f the Treg-deleted mice. Interestingly, chronic disease in treated mice appears to be due to the presence of Ac l -9 spe cific T cells. Thus, once self-tolerance to MBP is broken by immunization with the antigen in strong adjuvant, T C R peptide-specific CD4 Treg cells participate in reestablishing peripheral tolerance. Thus, a failure to generate Treg may be implicated in chronic autoimmune conditions.