Soluble HLA‐G molecules impair natural killer/dendritic cell crosstalk via inhibition of dendritic cells

Abstract

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.

CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

“…18 Both membranebound and soluble forms of HLA-G have been shown to prevent cytolytic T cells from carrying out antigen-specific cytolysis, inhibit the function of circulating NK cells, prevent CD4 ϩ T cells alloproliferating, 19 and inhibit maturation of dendritic cells. 20 In addition, Fournel et al demonstrated induction of apoptosis of CD8 ϩ T cells by soluble HLA-G (sHLA-G). 21 High level HLA-G expression was found in an increasing number of pathologic conditions, including hematologic and nonhematologic malignancies, on monocytes in HIV patients, and in autoimmune and inflammatory diseases.…”

Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

“…Indirect inhibitory immune effects of HLA-G could induce the generation cytotoxicity by interacting with the ILT2 inhibitory receptor (32)(33)(34)(35). We recently reported that NK cell cytolysis inhibited by HLA-G1 in an expression proportion-dependent manner, and HLA-G1 and HLA-G5 isoforms have an additive inhibitory effect on NK cytolysis (36,37 …”

Beyond the increasing complexity of the immunomodulatory HLA-G molecule

“…30 Finally, ILT2 and ILT4 differ at the level of the HLA-G structures they recognize: ILT2 is a receptor for HLA-G associated with ␤ 2 -microglobulin, whereas ILT4 also recognizes HLA-G free heavy chains. 30,31 Functionally, HLA-G1 inhibits the cytolytic function of uterine and peripheral blood NK cells, 32,33 the antigen-specific cytolytic function of cytotoxic T lymphocytes, 34 the alloproliferative response of CD4 ϩ T cells, 35,36 the proliferation of T cells and peripheral blood NK cells, [37][38][39] and the maturation and function of dendritic cells 40,41 (Table 1). Soluble HLA-G5 or soluble HLA-G1, which is generated by proteasomal cleavage from the cell membrane, has similar functions.…”