In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses

• T cell tolerance interferes with production of protective antibodies.
• Protective IgG2a/b anti-MOG Abs promote disease resolution during MOG EAE.
• Loss of IgG2a/b+ B cells and their Abs leads to pronounced disease exacerbation.
• Protective IgG2a/b+ B cells emanate from the marginal zone of the spleen.
• IgG2a/b+ B cell mediated protection is dependent on serum complement proteins.

F1 (SJL/J × C57BL/6) mice with MOG35–55-induced EAE recover from disease when treated with Ig-MOG carrying MOG35–55 peptide. However, Ig-PLP1, carrying PLP139–151, induced reduction of anti-MOG antibodies and exacerbated EAE. Herein, we show that Ig-PLP1 specifically reduces the frequency of B cells producing protective IgG2a/b anti-MOG antibodies. Surprisingly, these cells were marginal zone (MZ), rather than follicular (FO) or newly formed (NF), B cells and transfer of MZ B cells into sick mice nullified disease exacerbation by Ig-PLP1 in a complement dependent manner. These findings reveal a potential self-limiting regulatory mechanism involving auto-antibodies in MOG EAE.