HLA‐G promotes myeloid‐derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4

Abstract

Establishing and maintaining maternal-fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or preterm delivery. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that suppress T-cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA-G) is a major histocompatibility complex (MHC) I molecule with immune-modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA-G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR-MDSCs) express receptors for HLA-G, namely immunoglobulin-like transcript (ILT) 2 and 4, and that ILT4-expression by GR-MDSCs is regulated during pregnancy. Stimulation with soluble HLA-G (sHLA-G) increased suppressive activity of GR-MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine-2,3-dioxygenase (IDO) in myeloid cells. Effects of sHLA-G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA-G in humans as a potential mechanism for maintaining maternal-fetal tolerance. Modulating MDSC function during pregnancy via HLA-G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

“…Among these receptors, ILT2 is present on all monocytes and B lymphocytes, and on subsets of dendritic cells (DCs), myeloid derived suppressive cells (MDSCs), natural-killer (NK) cells and T cells ( 26 ). ILT4 is mainly expressed on DCs and monocytes, neutrophils and MDSCs ( 27 – 29 ); KIR2DL4 has been found predominately in decidual NK cells ( 30 ). Other receptors such as CD160 are expressed by subsets of CD8 + , CD4 + , Tγ/δ and CD56 dim NK cells, and by activated endothelial cells and intestinal intraepithelial cells.…”

“…Similar findings, such as the fact that HLA-G and paired immunoglobulin-like receptor B (PIR-B, murine homolog of human ILT receptors) engagement expanded the population of CD11b + Gr1 + PIR-B + MDSCs in an M8-HLA-G1 (human melanoma cell line) tumor-bearing mouse model, have also been reported ( 32 ). In addition to the murine models, a recent study by Köstlin et al ( 29 ) revealed that HLA-G/ILT4 interaction could promote MDSC accumulation and suppressive activity during human pregnancy.…”

The role of HLA‐G in parasitic diseases

“…HLA‐G can also indirectly play its immunomodulatory function through the generation of regulatory/suppressive cells. It has recently been shown that HLA‐G, through ILT4 interaction in maternal‐fetal interface, is able to generate myeloid‐derived suppressor cells which suppress CD8 + T cells cytotoxicity and maintains the maternal‐fetal tolerance . The presence of HLA‐G induces the differentiation of TCD4 + and CD8 + T cells into various subsets of regulatory cells that secrete IL‐10, transforming growth factor‐β, IL‐35 and HLA‐G5 .…”

“…It has recently been shown that HLA-G, through ILT4 interaction in maternal-fetal interface, is able to generate myeloid-derived suppressor cells which suppress CD8 + T cells cytotoxicity and maintains the maternal-fetal tolerance. 73 The presence of HLA-G induces the differentiation of TCD4 + and CD8 + T cells into various subsets of regulatory cells that secrete IL-10, transforming growth factor-β, IL-35 and HLA-G5. 74 The generation of regulatory/suppressive T cells is directly attributed to HLA-G since blocking this molecule during the initial stimulation by HLA-Gexpressing APCs prevents their generation, but HLA-G is not involved in their suppressive function.…”

Co-infecção Plasmodium falciparum e Schistosoma haematobium: papel dos genes HLA não-clássicos de classe I (HLA-G, -E e -F) na suscetibilidade à malária

“…Considering the IPD-IMGT/HLA v3.31.0 database, the HLA-G coding region evaluated here (positions -300 to +2838) generated 19 different haplotypes (Table 7), coding only four different (full length or truncated) proteins [G*01:01 (51.02%), G*01:03 (10.40 %), G*01:04 (27.19%) and G*01:05N (11.41%)]. Taken into account the well-recognized role of HLA-G as an immune checkpoint molecule, which is expressed in the placenta counteracting the mother immune system (Kovats et al 1990;Rouas-Freiss et al 1997;Allan et al 1999;Fournel et al 2000;Lila et al 2001;Petroff et al 2002;Ishitani et al 2003Ishitani et al , 2006Morandi et al 2010;Huang et al 2010;Baudhuin et al 2013;Naji et al 2014;Sampangi et al 2015;Grange et al 2015;Nazari and Farjadian 2016;Bian et al 2016;Eguchi et al 2016;K�stlin et al 2017), a low protein variability would be expected, reinforcing the hypothesis of a conserved coding region, due to the action of balancing selection in this region, as shown by the high Tajima's D (2.8, P = 0.0034). In addition, among the four most frequent haplotypes identified: G*01:01:02:01 (19.80%), G*01:04:04 (19.80), G*01:05N (11.41%) and G*01:03:01:02 (10.40%) ( Table 7), two of them (G*01:04:04 and G*01:05N) exhibited frequencies relatively higher than those observed worldwide (Castelli et al 2014a).…”