Soluble HLA-G and HLA-G1 Expressing Antigen-Presenting Cells Inhibit T-Cell Alloproliferation through ILT-2/ILT-4/FasL-Mediated Pathways

HLA-G is a tolerogenic molecule involved in maternal-fetal tolerance and in allograft acceptance. Soluble HLA-G proteins are present at high levels in plasma from transplanted patients who better accept their graft. In addition, infiltrating mononuclear cells expressing HLA-G can be detected within grafted tissues. To define the role of these HLA-G proteins in preventing graft rejection, we investigated the ability of HLA-G1 expressing antigen presenting cells (APC) and of soluble HLA-G proteins (i.e., HLA-G5 and shed HLA-G1) to inhibit T-cell alloproliferation and analyzed the molecules involved in such inhibition. Results demonstrated that both membrane-bound and soluble HLA-G proteins inhibited T-cell alloproliferation. This inhibition involved engagement of immunoglobulinlike transcript (ILT)-2 and ILT-4 receptors by HLA-G. Moreover, blocking Fas ligand (FasL) reversed HLA-G mediated inhibition, demonstrating that the Fas/FasL pathway is also recruited by HLA-G to exert its immunosuppressive function on T cells. These data highlight the role played by HLA-G in better graft acceptance status observed in transplanted patients with HLA-G+ grafted cells and high HLA-G plasma levels. Evidence to support such role in vivo was provided by the capacity of purified HLA-G5 from the plasma of the transplanted patient to suppress T-cell alloresponses.