Low‐dose interleukin‐2 promotes STAT‐5 phosphorylation, T(reg) survival and CTLA‐4‐dependent function in autoimmune liver diseases

CD4(+)CD25(high)CD127(low)forkhead box protein 3 (FoxP3(+)) regulatory T cells (T(reg)) are essential for the maintenance of peripheral tolerance. Impaired T(reg) function and an imbalance between effector and T(regs) contribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)−2, a cytokine essential for T(reg) survival and function. Consequently, few liver‐infiltrating T(reg) demonstrate signal transducer and activator of transcription‐5 (STAT‐5) phosphorylation. To establish the potential of IL‐2 to enhance T(reg) therapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT‐5 and the subsequent survival and function of T(reg) and T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, at less than 5 IU/ml, resulted in selective phosphorylation of STAT‐5 in T(reg) but not effector T cells or natural killer cells and associated with increased expression of cytotoxic T lymphocyte antigen‐4 (CTLA‐4), FoxP3 and CD25 and the anti‐apoptotic protein Bcl‐2 in T(reg) with the greatest enhancement of regulatory phenotype in the effector memory T(reg) population. VLDP also maintained expression of the liver‐homing chemokine receptor CXCR3. VLDP enhanced T(reg) function in a CTLA‐4‐dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination with clinical grade T(reg) in autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic T(reg).