Mitigation of experimental allergic encephalomyelitis by TGF-beta induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance.

Stimulation of naive T lymphocytes in the presence of IL-2 and TGF-beta induces the regulatory transcription factor Foxp3, which endows the cells with regulatory functions. To better understand the properties and therapeutic potential of these induced regulatory T cells (iTreg), we examined their immunomodulatory properties in myelin oligodendroglial glycoprotein-induced experimental allergic encephalomyelitis (MOG-EAE). Adoptively transferred iTreg were as potent as natural Foxp3+ Treg in preventing EAE development, and were active both prophylactically and after priming. The iTreg migrated into the CNS in quantity, skewing the ratio of regulatory to effector T lymphocytes. IL-10-/- iTreg failed to suppress disease, demonstrating a critical role for iTreg IL-10 production in their therapeutic activity. MOG-specific T cells from iTreg treated animals were anergic. The cells failed to proliferate in response to Ag except in the presence of exogenous IL-2, and did not secrete or secreted reduced amounts of IL-2, IFN-gamma, and IL-17. MOG-specific T cells were not wholly unresponsive though, as they did secrete IL-10 after stimulation. To determine whether iTreg-mediated tolerance was infectious, fostering the development of T lymphocytes that could independently suppress EAE, we purged draining lymph node cells from MOG-immunized, iTreg treated mice of the administered iTreg, and transferred the remaining cells to Ag-inexperienced mice. The transferred cells were able to block EAE development. Thus iTreg are highly potent suppressors of autoimmune encephalomyelitis, and act in an IL-10 dependent manner both through the induction of anergy in effector T cells and through the infectious induction of protective T lymphocytes able to independently suppress disease development.