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.

Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens

“…However, this physiology requires development of immunologic mechanisms whereby the semiallogeneic fetus escapes recognition by the maternal immune system. This requirement provides for the expression on the placenta of nonclassical MHC class I HLA-G, which stimulates inhibitory receptors on cells of lymphoid and myelomonocytic origin (54,55). It also selects for the production of immune inhibitory cytokines, PGs, and immunoregulatory T cells (56,57).…”

“…Three peptides corresponding to N-and C-terminal regions of PfP0 were synthesized and purified to 70-80% (Chiron, Clayton, Victoria, Australia). The peptides were designated N1 (DNVGSNQMASVRKSLR; codons 33-48), N2 (SV-RKSLRGKATILMGKNT; codons [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59], and C1 (AKADEPKKEE-AKKVE; codons 285-299) and correspond to T cell epitopes identified by lymphocyte proliferation responses of immunized mice (41). PHA (Sigma-Aldrich) or anti-CD3/28-coated T cell expander beads (Dynal) were used as positive controls.…”

HLA-G5 Induces IL-4 Secretion Critical for Successful Pregnancy through Differential Expression of ILT2 Receptor on Decidual CD4+ T Cells and Macrophages

“…Other candidates responsible for the cytokine profile of the decidual T cells could be molecules expressed/produced by trophoblasts. Soluble HLA-G5, secreted by the villous and extravillous cytotrophoblast that are, respectively, in direct contact with maternal blood of the intervillous space and maternal T cells in the decidua basalis (13), could be one of these.…”

Mechanisms of Maternal Immune Tolerance During Pregnancy

“…However, the antibody used to identify these antigens required MHC light chain and MHC heavy chain associations which are not present on all HLA-G isoforms. More recent studies using different antibodies which are capable of detecting previously undetectable HLA-G alleles showed that HLA-G isoforms are present throughout the placenta and within the chorion membrane, decidua and maternal blood (Hunt and Langat, 2009). …”

“…Early studies identified HLA class I antigen expression as being specific to extra-villous trophoblast (EVT) populations, with the proteins being prominent in cells adjacent to the decidua throughout gestation (Hunt and Langat, 2009). However, the antibody used to identify these antigens required MHC light chain and MHC heavy chain associations which are not present on all HLA-G isoforms.…”