HLA-G Level on Monocytoid Dendritic Cells Correlates With Regulatory T-Cell Foxp3 Expression in Liver Transplant Tolerance

Abstract

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. 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. 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. 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.