title: HLA-G level on monocytoid dendritic cells correlates with regulatory T-cell Foxp3 expression in liver transplant tolerance.
abstract: BACKGROUND
  Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule expressed as membrane-bound and soluble isoforms. Interaction of HLA-G with its receptor, immunoglobulin-like transcript 4 on dendritic cells (DCs) down-regulates their T-cell stimulatory ability.
  
  
  METHODS
  We examined expression of HLA-G, immunoglobulin-like transcript 4, other immune regulatory molecules (inducible costimulator ligand and glucocorticoid-induced tumor necrosis factor-related receptor ligand), and the activation marker CMRF44 on circulating monocytoid dendritic cell (mDC) and plasmacytoid dendritic cell by monoclonal antibody staining and flow cytometry. Three groups of stable liver transplant recipients: operationally tolerant (TOL), prospective immunosuppressive drug weaning, and maintenance immunosuppression (MI) were studied, together with healthy controls (HC). Serum HLA-G levels were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  In TOL patients, monocytoid dendritic cell (mDC) but not plasmacytoid dendritic cell expressed higher HLA-G than in MI patients or HC. In TOL patients, the incidence of CD4(+)CD25(hi)CD127(-) regulatory T cells (Treg) and the intensity of Treg forkhead box p3 (Foxp3) expression were significantly higher than in the MI group. HLA-G expression on circulating mDC correlated significantly with that of Foxp3 in the TOL group. There was no correlation between immunosuppressive drug (tacrolimus) dose or trough level and HLA-G expression or Treg frequency or Foxp3 expression. The incidence of patients with circulating HLA-G levels more than 100 ng/mL was highest in the TOL group, although statistical significance was not achieved.
  
  
  CONCLUSIONS
  Higher HLA-G expression on circulating mDC in TOL recipients compared with MI or HC, suggests a possible role of HLA-G in immune regulation possibly mediated by enhanced host Treg Foxp3 expression.
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Antonino
authors.initials: A
authors.lastname: Castellaneta
authors.forename: George V
authors.initials: GV
authors.lastname: Mazariegos
authors.forename: Navdeep
authors.initials: N
authors.lastname: Nayyar
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000097:blood*; D006680:HLA Antigens / Q000097:blood*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D060945:Inducible T-Cell Co-Stimulator Ligand; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D010414:Pennsylvania; D011971:Receptors, Immunologic / Q000097:blood; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance; D048069:Tumor Necrosis Factors / Q000097:blood; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C498514:ICOSLG protein, human; D007166:Immunosuppressive Agents; D060945:Inducible T-Cell Co-Stimulator Ligand; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors