Dendritic Cells Secrete the Immunosuppressive HLA-G Molecule upon CTLA4-Ig Treatment: Implication in Human Renal Transplant Acceptance

CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 +/- 14 ng/ml) than patients treated with calcineurin inhibitors (5 +/- 5 ng/ml) or healthy donors (5 +/- 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance. The Journal of Immunology, 2009, 183: 7054-7062.