HLA‐G molecules are known to exert immunosuppressive action on DC maturation and on NK cells, and can in consequence inhibit respectively T cell responses and NK cytolysis. In this study, we show that monocyte‐derived DC, differentiated in the presence of GM‐CSF and IL‐4, are sensitive to soluble (s) HLA‐G molecules during LPS/IFN‐γ maturation as demonstrated by the decrease of CD80 and HLA‐DR expressions and IL‐12 secretion. Moreover, DC pretreated with sHLA‐G were found to activate NK/DC crosstalk less than non‐treated DC. Early activation of NK cells co‐cultured with autologous DC was diminished as assessed by CD69 expression. The IFN‐γ production was impaired whereas a slight inhibition of the NK cell cytotoxicity against Daudi cell line was observed. Since sHLA‐G is expressed in grafts or sites of tumour proliferation, its indirect action on NK cells via DC could constitute a pathway of early inhibition for both innate and specific immune responses.

Summary Membrane‐bound and soluble human leucocyte antigen‐G (sHLA‐G) molecules display immunotolerant properties favouring tumour cell escape from immune surveillance. sHLA‐G molecules have been detected in several tumour pathologies; this study aimed to evaluate sHLA‐G expression in lymphoproliferative disorders. sHLA‐G plasma level was significantly increased in 110 of 178 newly diagnosed lymphoid proliferations cases i.e. 59% of chronic lymphocytic leukaemia, 65% of B non‐Hodgkin lymphomas (NHL) and 58% of T‐NHL. To assess the mechanisms involved in this secretion, the differential effect of cytokines was tested in in vitro cultures of NHL cells. A significant induction of sHLA‐G level was shown in T‐NHL in contrast with B‐NHL and normal equivalent cells, after cytokine stimulation with (i) interferonγ (IFNγ), interleukin‐2 (IL‐2) and granulocyte‐macrophage colony‐stimulating factor, (ii) IL‐10 and (iii) transforming growth factor β. An impact of microenvironment on sHLA‐G expression was found in B‐NHL as shown by the in vitro effect of addition of normal monocytes. Finally, a functional effect of sHLA‐G molecules purified from pathologic plasma was demonstrated by their strong capacity to inhibit T‐cell proliferation at concentrations currently observed during these disorders. These results suggest that functional sHLA‐G molecules are upregulated in lymphoproliferative disorders which can support their potential immunomodulatory role during this pathology.

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Haematopoietic stem cell transplantation is often complicated by the life-threatening graft-versus-host disease (GVHD) which consists of an allogeneic reaction of the graft cells against the host organs. The aim of this study was to investigate the putative involvement of soluble human leucocyte antigen (sHLA) class I molecules, and particularly sHLA-G molecules, in the occurrence and/or prevention of acute GVHD (aGVHD) in allogeneic peripheral blood stem cell (PSC) transplantation. Whole sHLA class I molecules seem to be involved in aGVHD pathogenesis because detection of a high concentration of these molecules in the first month post allograft is correlated with aGVHD occurrence. Conversely, a high level of sHLA-G molecules before and after allograft could indicate good prognosis in PSC allograft transplantation. sHLA-G molecules seem to be involved in aGVHD prevention, not only because they are enriched in plasma of patients without aGVHD, but also because: (i) a positive correlation has been found between sHLA-G level and CD4+ CD25+ CD152+ natural regulatory T cell (T(reg)) frequency in the blood of transplanted patients; and (ii) the presence of CD4+ CD25+ CD152+ natural T(reg) is correlated with increased sHLA-G expression in in vitro mixed leucocyte reaction cultures. Altogether, these results support the immunomodulatory function of sHLA-G molecules that might create a regulatory network together with the natural T(reg) to foster the induction of a tolerogenic environment and improve PSC transplantation favourable outcome.