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

Summary 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 .