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-gamma production. In addition, transforming growth factor-beta (TGF-beta) was shown to be involved in the recovery from EAE as the percentage of CD4(+) cells expressing TGF-beta 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-beta 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-beta plays an important role.