Low-dose interleukin-2 promotes STAT-5 phosphorylation, T_reg survival and CTLA-4-dependent function in autoimmune...

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 .