Recovery from experimental allergic encephalomyelitis is TGF-β dependent and associated with increases in CD4⁺LAP⁺ and CD4⁺CD25⁺ T cells

SJL mice are highly susceptible to proteolipid protein (PLP) 139-151-induced experimental allergic encephalomyelitis (EAE). The disease is characterized by a relapsing-remitting type of paralysis. However, the mechanism by which animals recover from EAE is poorly understood. Here, we investigated the role of regulatory T cells in the recovery from disease. We found that Forkhead box P3-expressing CD4⁺CD25⁺ T cells were increased in the blood, draining lymph node and spleen of EAE-recovered SJL mice. These cells were anergic and inhibited proliferation of CD4⁺ CD25^- T cells to PLP 139-151 or anti-CD3 antibody stimulation. Depletion of CD4^-CD25⁺ T cells during the recovery phase exacerbated disease, resulted in the expansion of IA^s/PLP 139-151-tetramer-positive cells and enhanced IFN-γ production. In addition, transforming growth factor-β (TGF-β) was shown to be involved in the recovery from EAE as the percentage of CD4⁺ cells expressing TGF-β latency-associated peptide (LAP) on the cell surface increased significantly in blood and spleen of EAE-recovered mice as compared with the naive mice and in vivo neutralization of TGF-β abolished recovery from disease. Taken together, our results demonstrate that both CD4⁺CD25⁺ and CD4⁺LAP⁺ regulatory T cells mediate recovery from PLP 139-151-induced EAE in SJL mice in which TGF-β plays an important role.