Low dose interleukin-2 promotes STAT5 phosphorylation, Treg survival and CTLA-4 dependent function in autoimmune liver disease: Low dose IL2 promotes regulatory T cell function in autoimmune liver diseases

CD4+CD25highCD127lowFOXP3+ regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Impaired Treg function and an imbalance between effector and regulatory T cells contribute to the pathogenesis of autoimmune diseases. We recently reported that the hepatic microenvironment is deficient in IL-2, a cytokine essential for Treg survival and function. Consequently, few liver-infiltrating Treg demonstrate STAT5 phosphorylation.
To establish the potential of IL-2 to enhance Treg therapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT5 and the subsequent survival and function of Treg and T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, less than 5 IU/ml, resulted in selective phosphorylation of STAT5 in Treg but not effector T cells or natural killer cells and associated with increased expression of CTLA-4, FOXP3 and CD25 and the antiapoptotic protein Bcl-2 in Treg with the greatest enhancement of regulatory phenotype in the effector memory Treg population. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Treg function in a CTLA-4 dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination wit clinical grade Treg in autoimmune liver diseases as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic Treg.