Soluble HLA-G protein secreted by allo-specific CD4⁺T cells suppresses the allo-proliferative response: A CD4⁺T cell regulatory mechanism

Abstract

We recently reported that the nonclassical HLA class I molecule HLA-G was expressed in the endomyocardial biopsies and sera of 16% of heart transplant patients studied. The aim of the present report is to identify cells that may be responsible for HLA-G protein expression during the allogeneic reaction. Carrying out mixed lymphocyte cultures in which the responder cell population was depleted either in CD4 ؉ or CD8 ؉ T cells, we found that soluble HLA-G5 protein but not the membrane-bound HLA-G isoform was secreted by allo-specific CD4 ؉ T cells from the responder population, which suppressed the allogeneic proliferative T cell response. This inhibition may be reversed by adding the anti-HLA-G 87G antibody to a mixed lymphocyte culture. That may indicate a previously uncharacterized regulatory mechanism of CD4 ؉ T cell proliferative response.

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

“…In particular, soluble HLA-G induces apoptosis of CD8 + T and NK cells and may participate in allograft tolerance through peripheral deletion of alloreactive T cells after allotransplantation in vivo [21,22]. Previous analysis of the functional role of both HLA-G1 and HLA-G5 in mixed lymphocyte reaction showed that both suppress the alloproliferative response of T cells [23,24,29]. Such inhibition could be reversed by the use of anti-HLA-G mAb [24].…”

“…Previous analysis of the functional role of both HLA-G1 and HLA-G5 in mixed lymphocyte reaction showed that both suppress the alloproliferative response of T cells [23,24,29]. Such inhibition could be reversed by the use of anti-HLA-G mAb [24].…”

“…Since HLA-G inhibits T cell functions [23,24], we analyzed the T cell alloproliferative response of the sixteen allogeneic combinations after 6 days of MLR. Strong proliferative responses were observed for all these allogeneic combinations.…”

A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

“…The resulting protein has a novel carboxyl terminus and is able to complex with ␤ 2 -microglobulin, but would be released from the cell due to the lack of a transmembrane domain (12,13). In addition to the placenta (14,34), soluble HLA-G has also been reported in CD4 ϩ T cells (20), activated monocytes (35), thymic epithelium (36), and lung tumor cells (37). It is intriguing that like HLA-G, the Mamu-AG gene also is alternatively spliced to give rise to a soluble molecule.…”

“…Unexpectedly, soluble HLA-G was detected not only in pregnancy, but also in nonpregnant women as well as males. Recent studies suggested that HLA-G5, one isoform of soluble HLA-G, can induce apoptosis in peripheral CD8 ϩ T cells via a Fas-Fas ligand mechanism (19), can suppress an allogeneic proliferative T cell response in mixed lymphocyte cultures (20), and can inhibit peripheral blood NK cell-mediated cytotoxicity (21). These results collectively suggest that while membrane-bound HLA-G may interact with resident leukocytes within the decidua, soluble HLA-G may act on blood cells in the peripheral circulation in both pregnant and nonpregnant individuals.…”