Low-dose interleukin-2 promotes STAT-5 phosphorylation, Tregsurvival and CTLA-4-dependent function in autoimmune liver diseases.
CD4+CD25highCD127lowforkhead box protein 3 (FoxP3+) regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Impaired Tregfunction and an imbalance between effector and Tregscontribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)-2, a cytokine essential for Tregsurvival and function. Consequently, few liver-infiltrating Tregdemonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation. To establish the potential of IL-2 to enhance Tregtherapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT-5 and the subsequent survival and function of Tregand 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 Tregbut 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 Tregwith the greatest enhancement of regulatory phenotype in the effector memory Tregpopulation. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Tregfunction in a CTLA-4-dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination with clinical grade Tregin autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic Treg.
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.
H C
HC
Jeffery
Institute of Metabolism and Systems Research, University of Birmingham, UK.
L E
LE
Jeffery
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.
P
P
Lutz
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.|Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK.
M
M
Corrigan
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.|Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK.
G J
GJ
Webb
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.|Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK.
G M
GM
Hirschfield
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.|Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK.
D H
DH
Adams
Centre for Liver Research and National Institute for Health Research Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, UK.|Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK.
Y H
YH
Oo
D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008107:Liver Diseases / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; C082598:aldesleukin
Bcl-2; CTLA-4; STAT-5; autoimmune liver disease; interleukin-2; regulatory T cells