T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We previously showed in C57BL/6 mice that part of the CD4 super(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4 super(+) T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG sub(35-55)-reactive CD4 super(+) T cells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M sub(15-35) by I-A super(b) on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M sub(15-35) (NF-M sub(15-35)T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self-antigens. In the absence of Myelin oligodendrocyte glycoprotein (MOG), CD4 T cells are not tolerized leading to increased Teff/Treg ratio, and enhanced inflammatory response in MOG super(-/-)NF-M super(-/-) animals. Absence of such tolerization results in increased encephalitogenic properties.