Our recent research focus has been on the immune tolerance maintained by regulatory T cells and on the resolution of inflammation. Regulatory T cells are CD4+Foxp3+ T cell subset that maintain immune tolerance by suppressing excess activation of effector T cells, B cells and myeloid cells. We and others have shown that fragility in regulatory T cells alone confers severe systemic inflammation and possible lethality. We delineated the mechanisms underlying the plasticity of regulatory T cells, focusing on their conversion into IFN-γ and IL-17-secreting T cells, especially under infection-induced inflammation. Re-programming of regulatory T cells into inflammatory T cells in autoimmune disease may not be readily visible by phenotypes, but could be detected by transcriptome analysis. We identified HIF-1α as one of the factors controlling the function of regulatory T cells, and characterized several pathways antagonizing HIF-1α. We further developed new approach to maintain the stability of regulatory T cells through neutralization IL-6. The potential application of regulatory T cells manipulation in immunotherapy will be discussed.