The role of Foxp3+ regulatory T cells during glucocorticoid treatment of autoimmunity

Treatment with synthetic glucocorticoids (GC) has been the frontline approach to treat inflammatory diseases. In the context of multiple sclerosis (MS), an autoimmune inflammatory disorder in the central nervous system mediated by myelin antigen reactive CD4 T cells, high dose steroid therapy (e.g., intravenous methylprednisolone) is effective in downregulating acute relapses and in hastening the recovery from the relapses. Despite the broad usage of GCs, our understanding the underlying mechanism is disappointingly limited. One potential drawback behind GC therapy is that not all patients are responsive to the treatment and they often acquire the status of non-responsiveness, GC resistance. Increasing the doses raises significant health concerns due to wide-ranging adverse side-effects. Therefore, it is imperative to define the precise mechanisms by which GC modulates inflammatory responses. GC exerts its immunotherapeutic actions by binding its cytosolic receptor, GC receptor (GR, encoded by the Nr3c1 gene), which upon ligand binding undergoes conformational changes, translocates into the nucleus, and acts as transcription repressors/activators. It was previously reported that systemic dexamethasone (Dex) administration reduces the severity of experimental autoimmune encephalomyelitis (EAE), an animal model for MS and that T cells are the primary targets of therapeutic actions of Dex, because T cell-specific GR-/- (Lck-Cre Nr3c1-floxed) animals fail to respond to the Dex treatment, while GR deletion on myeloid compartments (LysM-Cre Nr3c1-floxed animals) does not affect Dex-induced treatment of EAE. Foxp3+ regulatory T cells (Treg) are a CD4 T cell subset critically involved in inflammation and tolerance. Lack of Tregs results in systemic autoimmune inflammation. Multiple mechanisms have been proposed to account for regulatory functions of Tregs in vivo, and this is an area of active investigation because the mechanisms appear to be tissue- and disease-specific. O