Foxo proteins control gene expression during many cellular processes including cell cycle progression, reactive oxygen species detoxification, survival and death. During viral infection, we demonstrated that Foxo3 critically down-regulates the magnitude of the anti-viral T cell response by constraining the production of key inflammatory cytokines by dendritic cells (DCs). This impact on the innate immune response suggests that Foxo3 is likely to control the intensity of the adaptive immune response irrespective of its nature. We therefore analyze the implication of Foxo3 in the susceptibility to central nervous system inflammation. We showed that mice deficient in Foxo3 are remarkably resistant to experimental autoimmune encephalomyelitis (EAE), a common mouse model for multiple sclerosis. We showed that the reduced severity to EAE of Foxo3 deficient mice is not the consequence of an impaired priming of CD4 T cells in response to immunization. Rather, Foxo3 appears to play a role in the regulation of Th17 and Th1 differentiation. Thus, the reduced severity of EAE in Foxo3 deficient mice may be related to the inability of Foxo3-deficient CD4 T cells to differentiate into encephalogenic T cells. By dissecting the cellular mechanism involved in this phenotype, we showed that Foxo3 plays crucial role in both DC and T cells. Understanding Foxo3 function will bring new insights into the mechanisms that support immune cell homeostasis during normal and pathologic immune responses.
- Copyright © 2013 by The American Association of Immunologists, Inc.