Alloreactive CD4⁺ and CD8⁺ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

Abstract

HLA‐G displays immunotolerogenic properties towards the main effector cells involved in graft rejection through inhibition of NK‐ and CTL‐mediated cytolysis and CD4+ T cell alloproliferation. HLA‐G expression is restricted in healthy tissues to trophoblast and thymus but is extended to various tissues under pathological conditions. HLA‐G was detected in allograft biopsies and sera from transplanted patients who displayed a better graft acceptance. However, the cells involved in such de novo expression of HLA‐G remain to be characterized. By flow cytometry and confocal microscopy, we demonstrated that, following allogeneic stimulation in vitro, both CD4+ and CD8+ T cell subsets can express membrane‐bound HLA‐G1 and/or soluble HLA‐G5molecules. Such HLA‐G1/‐G5 expression is regulated at the transcriptional level. Soluble HLA‐G5 could be detected by using a novel monoclonal antibody, 5A6G7, specific for the intron 4‐retaining sequence of HLA‐G5. Finally, the biological relevance of these data was provided by analysis of transplanted patients in whom we identified both CD4+ and CD8+ T cells expressing HLA‐G. The HLA‐G‐positive T cells we describe here may constitute a cellular source of HLA‐G after allotransplantation and may be involved in the improved graft acceptance which is observed in HLA‐G‐positive transplanted patients.

HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+T cells

“…Shed HLA-G1 (sHLA-G1) concentrations in cell-free supernatants of mock-and HLA-G1-transfected cell lines were measured with an HLA-G1-specific sandwich ELISA by using anti-HLA-G1͞G5 MEM-G͞09 mAb for capture, and anti-human ␤2-microglobulin was conjugated to horseradish peroxidase for detection as described (27).…”

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

“…ϩ -and CD8 ϩ -activated T cells and inducing suppressor T cells (25)(26)(27)(28). In human allotransplantation, HLA-G has been detected in vivo in plasma and grafts from kidney (29), liver (30), and combined liver-kidney (31) transplant patients who experienced better graft acceptance.…”

Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites

“…35,36 Here, we described for the first time a significantly higher frequency of HLA-G pos blood cells after allo-HCT as compared to pre-transplant values and healthy subjects. Interestingly, there was a more pronounced expansion of CD3 + HLA-G pos cells (5.4-fold increase) compared to the increase in CD14 + HLA-G pos cells (2.2-fold increase).…”

“…Similarly to the liver/kidney transplanted patients, the HLA-Gpos T cells after allo-HCT were mainly CD8 + . 36 What regulates this expansion of HLA-G pos cells in the bone marrow transplanted patients is not known. The fact that increased HLA-G pos cells appeared early post-transplantation and remained high also at later time points after transplantation makes it very likely that the alloreactive environment in the transplanted patient played a causative role in the long-term expansion of the peripheral blood HLA-G pos cells.…”

“…Indeed, there are data suggesting that an alloreaction itself might up-regulate the HLA-G expression. 36 In the only study analyzing the role of HLA-G in the allo-HCT setting, Le Maux et al 15 found increased soluble HLA-G plasma levels in patients without acute GvHD as compared to those patients with, and suggested a preventative role of this molecule in the occurrence of acute GvHD. In our study, we did not find any correlation between the frequency of the HLA-G pos cells and active GvHD, history of acute or chronic GvHD, severity of chronic GvHD or treatment with immunosuppressive drugs.…”