Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity

Abstract

The immunosuppressive function of regulatory T (T_reg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of T_reg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from T_reg cell paucity, highlighting a vital function of T_reg cells in preventing fatal autoimmune inflammation. However, a major question remains whether T_reg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate T_reg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued T_reg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, T_reg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.