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

• Published in: Haematologica (Roma) Vol. 97; no. 9; pp. 1338 - 1347
• Main Authors: LAZANA, Loanna, ZOUDIARI, Anastasia, KOKKINOU, Dimitra, THEMELI, Maria, LIGA, Maria, PAPADAKI, Helen, PAPACHRISTOU, Dionysios, SPYRIDONIDIS, Alexandros
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01-09-2012
• Subjects: Biological and medical sciences; Bone Marrow Transplantation - adverse effects; Case-Control Studies; Flow Cytometry; Graft vs Host Disease - blood; Graft vs Host Disease - etiology; Hematologic and hematopoietic diseases; HLA-G Antigens - blood; Humans; Immune Tolerance - immunology; Medical sciences; Original and Brief Reports; Prognosis; Transplantation, Homologous; Human; Immunopathology; Graft versus host disease; HLA-System; Hematology; Stem cell; Major histocompatibility system; Hematopoietic cell; Homograft; GvHD; Myeloid cell; HLA-G; De novo; Blood; Allogeneic hematopoietic stem cell transplantation; HLA-A-Locus; Graft; Suppressive cell; Expansion; Class I histocompatibility antigen; myeloid suppressor cells
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2011.055871

The human leukocyte antigen-G (HLA-G) has been considered to be an important tolerogeneic molecule playing an essential role in maternal-fetal tolerance, which constitutes the perfect example of successful physiological immunotolerance of semi-allografts. In this context, we investigated the putative role of this molecule in the allogeneic hematopoietic cell transplantation setting.
The percentage of HLA-G(+) cells in peripheral blood of healthy donors and allo-transplanted patients was evaluated by flow cytometry. Their immunoregulatory and tolerogeneic properties were investigated in in vitro immunostimulatory and immunosuppression assays. Immunohistochemical analysis for HLA-G expression was performed in skin biopsies from allo-transplanted patients and correlated with the occurrence of graft-versus-host disease.
We identified a CD14(+)HLA-G(pos) population with an HLA-DR(low) phenotype and decreased in vitro immunostimulatory capacity circulating in peripheral blood of healthy individuals. Naturally occurring CD14(+)HLA-G(pos) cells suppressed T-cell responses and exerted an immunotolerogenic action on T cells by rendering them hyporesponsive and immunosuppressive in vitro. After allogeneic hematopoietic cell transplantation, HLA-G(pos) cells increase in blood. Interestingly, besides an increase in CD14(+)HLA-G(pos) cells, there was also a pronounced expansion of CD3(+)HLA-G(pos) cells. Of note, CD3(+)HLA-G(pos) and CD14(+)HLA-G(pos) cells from transplanted patients were suppressive in in vitro lymphoproliferation assays. Furthermore, we found an upregulation of HLA-G expression in skin specimens from transplanted patients that correlated with graft-versus-host disease. Inflammatory cells infiltrating the dermis of transplanted patients were also HLA-G(pos).
We report the presence of naturally occurring HLA-G(pos) monocytic cells with in vitro suppressive properties. HLA-G expressing regulatory blood cells were found in increased numbers after allogeneic transplantation. Epithelial cells in skin affected by graft-versus-host disease revealed elevated HLA-G expression.