HLA-G: a human pregnancy-related immunomodulator

Abstract

In human pregnancies mothers and their embryo/fetuses are invariably genetically different. Thus, attenuation of the adaptive maternal immune response, which is programmed to reject 'foreign' entities, is required for pregnancy to be initiated and maintained. Unexpectedly, given the propensity of the immune system to dispose of non-self entities, at least 50% of expected human pregnancies reliably go forward. This indicates that to a large extent, effective systems of tolerance have evolved. Although overlapping and redundant mechanisms of tolerance have been identified, production of HLA-G by trophoblast cells derived from the external trophectoderm layer of the blastocyst appears to be of major importance. At this point in time, no pregnancies in which all of the proteins derived from the HLA-G gene are absent have as yet been reported. Many studies have shown that both membrane-bound and soluble isoforms of the proteins derived from this HLA class Ib gene are produced by placental trophoblast cells, with consequences that include but are not restricted to immune suppression at the maternal-fetal interface. Here we report new studies that are leading to a better understanding of the HLA-G proteins, their unique structures, unusual modes of regulation, diverse functions, and potential for use in diagnostic and therapeutic procedures related to suboptimal fertility in women.

Figure 1. Products of the fetal placenta drive tolerance in the pregnant uterus

The fetal placenta is directly apposed and in contact with the decidua throughout pregnancy. Placental cells exhibit cell surface molecules and synthesize soluble substances that program a tolerant phenotype in maternal immune cells in the adjacent decidua.

Figure 2. Recombinant HLA-G produced in HEK293 cells does not kill CD14+ blood monocytes

CD14+ blood monocytes incubated for 48 hr with 100 nM/ml of recombinant HLA-G5 or HLA-G6 (or no HLA-G) generated in HEK293 cells showed little change. Although some statistical significance suggesting increased cell numbers, the changes were not dramatic.

Figure 3. A schematic drawing illustrating the effects of recombinant HLA-G5 on resting and IFNγ-activated blood monocytes

After 48 hr of incubation with HLA-G5 CD14+ cells that were resting (no IFNγ) demonstrated diminished synthesis of TNFα and IL-1 β in comparison with untreated cells but levels of IL-6 and the anti-inflammatory cytokine, IL-10, were unchanged. By contrast, when the cells were activated with 100 U/ml of IFNγ and simultaneously treated with recombinant HLA-G5 there were a modest increases in levels of TNFα and IL-1 β but a dramatic increase in the anti-inflammatory cytokine, IL-10. The data shown represent values obtained in one of three similar assays.