Myelin Proteolipid Protein-Specific CD4+ CD25+ Regulatory Cells Mediate Genetic Resistance to Experimental Autoimmune Encephalomyelitis

SJL mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139–151, whereas H-2 congenic B10.S mice are resistant. Immunodominance and susceptibility to EAE are associated with a high precursor frequency of PLP 139–151-specific T cells in the naive repertoire of SJL mice. To understand the mechanism of EAE resistance in B10.S mice, we determined the precursor frequency of PLP 139–151-reactive T cells in both strains by using IAs/PLP 139–151 tetramers. SJL and B10.S mice had similar frequencies of tetramer-reactive T cells in the naive peripheral repertoire. However, in SJL mice, the majority of PLP 139–151 tetramer-positive cells were in the CD4+ CD25+ population, whereas there were more tetramer-positive cells in the CD4+ CD25+ population of B10.S mice. Depletion of CD4+ CD25+ cells in vivo facilitated the expansion of PLP 139–151-reactive cells with production of T helper 1 cytokines in EAE-resistant B10.S mice. Furthermore, anti- CD25 Ab treatment before immunization resulted in EAE induction in these otherwise resistant mice. These data indicate an important role for autoantigen-specific CD4+ CD25+ cells in genetic resistance to autoimmunity