Immune modulation of HLA-G dimer in maternal-fetal interface

Abstract

HLA-G is a non-classical human MHC class I molecule, which has several characteristics distinct from classical MHC, such as low polymorphism and restricted tissue distribution. HLA-G is expressed on placenta, thymus and some tumors. At the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (MHCI), HLA-A and -B, to prevent normal T cell responses. Instead, HLA-G is expressed and can suppress a wide range of immune responses by binding to inhibitory immune cell surface receptors, such as leukocyte Ig-like receptor (LILR) B1 and LILRB2. HLA-G exists in various forms, including beta2m-associated or -free disulfide-linked dimers that can be expressed either at the cell surface or in soluble form. However, until recently the physiological role of these different molecular forms has been unclear. In this issue of the European Journal of Immunology, one article demonstrates that the disulfide-linked homodimer of beta2m-associated HLA-G is the major fraction expressed by trophoblast cells. The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells by principally binding to LILRB1. On the other hand, another recent report showed that beta2m-free disulfide-linked HLA-G dimers are produced by villous cytotrophoblast cells. Taken together, these results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction. See accompanying article: (http://dx.doi.org/10.1002/eji.200737089).

Figure 1

Receptor recognition of the different forms of HLA-G at the maternal-fetal interface. HLA-G can be expressed in various forms in placenta. The structures of β2m-associated HLA-G monomer and dimer are shown. LILRB1 (light blue), which is expressed on decidual antigen-presenting cells (APC) and subsets of NK and T cells, binds to only β2m-associated forms of HLA-G monomer and dimer. LILRB2 (dark blue), whose expression is restricted to decidual APC, binds to both β2m-associated and -free forms of HLA-G monomer and dimer. LILRB1 and LILRB2 presumably bind to HLA-G dimer more strongly than its monomer. The thickness of the arrows corresponds to the signal strength. Both membrane-bound and soluble forms likely inhibit the immune responses of LILRB-expressing cells. On the other hand, the HLA-G recognition of CD160 and KIR2DL4 still remains unclear.