Previous work demonstrated that EAE induced by recombinant human MOG was B cell-dependent. Data presented here reveal a T cell response to MOG61-85 in human rMOG-immunized B cell(-/-) mice not observed in WT mice. Further study revealed this peptide to be a cryptic epitope in WT mice. Co-immunization of B cell(-/-) mice with MOG35-55 and MOG61-85 peptides led to less severe disease compared to mice immunized with MOG35-55 alone. Disease amelioration was associated with decreased production of Interferon- by lymph node cells. Thus, MOG61-85 represents a protective epitope to human rMOG induced EAE in B cell(-/-) mice.