Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture

Abstract

Exquisitely regulated cytokine balance during early pregnancy is thought to be necessary for promoting survival of the fetal allograft. Our previous studies have demonstrated that membrane-bound human leukocyte antigen (mHLA-G) expressed on trophoblasts is one of the key factors in regulating cytokine balance by shifting the Th1/Th2 balance toward Th2 polarization, a favourable milieu for the maintenance of pregnancy. Given that trophoblasts secrete soluble HLA-G (sHLA-G), we examined its biological roles in comparison with mHLA-G. We cultured peripheral blood mononuclear cells (PBMC) with either the HLA-A and -B-deficient B lymphoblast cell line (721.221 cells) or the same cell line transfected with mHLA-G (721.221-G1 cells), in the presence or absence of recombinant sHLA-G. Cytokine concentrations in the culture media were determined by enzyme-linked immunosorbent assay. In contrast to mHLA-G protein, sHLA-G stimulated the release of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, whereas it reduced the release of interleukin (IL)-3, regardless of the presence of the presence of a stimulatory effect of the mHLA-G-expressing cells. Although mHLA-G reduced the release of IL-4, sHLA-G did not have any effect. Conversely, sHLA-G stimulated the release of IL-10 whereas mHLA-G was without effect. These results suggest that sHLA-G regulates the release of cytokines from PBMC chiefly by counterbalancing mHLA-G, and thereby may play a role in maintaining pregnancy.

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

“…22,25 The explanation for this discrepancy might be that others treated peripheral T cells rather than decidual T cells with trophoblast-cultured supernatant, rather than direct coculture with the trophoblast. Our unpublished data show similar effects of trophoblasts and DSCs on peripheral immune cells.…”

“…[23][24][25][26] In the present study, we investigated how this axis was involved in the development of the Th2 bias at the maternal/fetal interface. As shown in Figure 4a, treatment with anti-CXCR4 antibody significantly inhibited IL-4 and IL-10 secretion in all cultures, especially in coculture of two or three cell types.…”

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

“…A role in controlling T cell expansion, blocking CTL activity, and inducing apoptosis in alloreactive T cells has been suggested for soluble HLA-G (19,20,44). Alternatively, soluble Mamu-AG might also help prevent antisperm immune responses following minor breaks in the bloodtestis barrier of the seminiferous basement membrane.…”

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

“…Conversely, activation of NK cells depends on the lack of MHC expression in the target cells, but extravillous cytotrophoblast HLA-G expression induces IL-10 and other cytokines, which build a favorable milieu for pregnancy maintenance. 38 Thus, the trophoblast resists NK cell and CD8 þ lysis by disturbed antigen recognition through HLA-G, although low diversity peptides are presented by HLA-G to cytotoxic T lymphocytes. 38 Nothing is known about T. gondii antigen presentation through HLA-G, but it would induce limited CD8 þ lysis of infected cells and Th1-type inflammation during early pregnancy, which would partially favor local parasite control and implantation success.…”