Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg 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.