Dysfunction of IL-10-producing type 1 regulatory T cells and CD4(+)CD25(+) regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys

Abstract

CD4(+)CD25(+) Treg and IL-10(+) Tr1 cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Dysfunction of Tregs appears to be a critical factor in the pathogenesis of autoimmune diseases. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of CNS, where CD4(+) T cells result in nervous tissue damage. The aim of this study was to investigate the protective role of Treg and Tr1 cells in a mimic model of human MS in Cynomolgus monkeys. This study indicated the suppressive capacity of Tregs from MS monkeys was impaired compared with naive controls. The population of CD4(+)CD25(+) Tregs was decreased in acute stage of MS. However, they showed a restored function and percentage in remitting monkeys. In stable phase, CD4(+)CD25(+) Tregs differentially expressed elevated level of CD62P cell adhesion molecule which contributes to the mechanism by which Treg cells inhibit CD4(+) T cell responses. On the other hand, the percentage of CD4(+)IL-10(+) Tr1 and suppressive function of Tr1 cells were found reduced in MS monkeys. IL-10 secretion was diminished almost 9-fold in active MS, and recovered in active MS. This deficit in IL-10 secretion was specific to CD3/CD46, but not to CD3/CD28 stimulation. The concentrations of IFN-gamma secreted by CD3/CD46-activated T cells were also not affected. These results demonstrate that Tregs are dysfunctional in Cynomolgus monkey with MS. Loss of regulatory function appears to be an important factor in the pathogenesis of MS. Hence, to develop new approaches for induction of Tregs in vivo may be beneficial for the clinical treatment in autoimmune diseases.