SJL mice immunized with proteolipid protein (PLP) develop relapsing experimental autoimmune encephalomyelitis (R-EAE). R-EAE is a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CNS) that is used as a model for the human disease multiple sclerosis (MS). Previous studies showed that young (< 8 weeks) male SJL mice were resistant to active induction of EAE with CNS homogenate, while female mice were susceptible. We have recently observed that young male SJL mice immunized with a major encephalitogenic peptide of myelin, PLP 139-151, developed initial clinical and histological symptoms of EAE with a severity similar to age-matched females; however, unlike females, male mice did not relapse. Significant T cell proliferation to PLP 139-151, but not to other PLP and myelin basic protein (MBP) epitopes, was observed in both males and females during the initial episode, recovery, and first relapse of clinical disease. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of lymphokine mRNA revealed differences in IFN-gamma and IL-4 synthesis consistent with the hypothesis that Th2 T cells develop in young male SJL mice that regulate the relapsing phase of the disease. These data suggest that immunization of young male SJL mice with PLP 139-151 overrides a defect in antigen presentation responsible for the previously observed resistance to EAE, and that natural processing and presentation of neuroantigens during the course of acute EAE induces Th2 cells that prevent the relapse of disease.