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

Abstract

Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto–maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4+ T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4+ T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4+ T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy.

M1/M2 Macrophage Polarity in Normal and Complicated Pregnancy

“…This, in part, is caused by the uneven spatial distribution of neighboring leukocytes and trophoblasts within the decidua, which provide different cues to resident macrophages. Events that account for these changes include the contribution of immunoregulatory molecules from trophoblasts such as HLA-G (68, 69), TGF-β (40), and VIP (41). These compounds have direct effects on macrophages or on Tregs, which express pro-M2 factors such as IDO and IL-10 (1).…”

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

“…Nowadays, it is widely accepted that neurodegeneration is one of the principal hallmarks of HAND that occurs without neuronal infection. Brain degeneration and consequently neuronal apoptosis is triggered by signaling of viral products such as Tat and gp120 (Kaul and Lipton 1999; Bansal et al 2000; Gurwell et al 2001; Kaul et al 2001; Hisaka et al 2004; Thomas et al 2009; Merino et al 2011; Zhang et al 2011), cytokines and chemokines (Lee et al 2011; Vazquez-Valls et al 2011; Yan et al 2011; Johansson et al 2013; Lombardelli et al 2013), or by toxins produced from infected macrophages including lysosomal protease cathepsin B(Ciborowski and Gendelman 2006; Tian et al 2008; Turchan-Cholewo et al 2009; Sun et al 2010; Luo et al 2010; Rodriguez-Franco et al 2012; Tovar-Y-Romo et al 2013; Malla et al 2014). Furthermore, studies demonstrated that cocaine can amplify the immune response and cause neuroinflammation (Clark et al 2013) via dysfunction of the BBB (Dhillon et al 2008; Gandhi et al 2010) through alterations of tight junction proteins (Dhillon et al 2007), increased glial activation, and induction of neuroinflammatory pathways (Yao et al 2011; Kousik et al 2012).…”

Cumulus oophorus T cells: a possible source of follicular fluid G-CSF, biomarker predictive for embryo implantation in IVF/ICSI cycles

“…Accordingly, at endometrial level, IL-4 is crucial for endometrial receptivity of conceptus and thus the success of pregnancy. The IL-4 produced by decidual CD4+ effector T cells by inducing tolerance towards the HLA-C antigens from paternal origins present on trophoblast, likening the later to a semiallograft, decreases in unexplained recurrent abortions, (25,31). Since G-CSF induces the increased T cell IL-4 production (26), which is crucial for the success of pregnancy (25,31), T cell IL-4 production induced in response to the treatment with G-CSF of patients with unexplained recurrent miscarriages, could explain the increased live-birth rates in these patients.…”

“…The IL-4 produced by decidual CD4+ effector T cells by inducing tolerance towards the HLA-C antigens from paternal origins present on trophoblast, likening the later to a semiallograft, decreases in unexplained recurrent abortions, (25,31). Since G-CSF induces the increased T cell IL-4 production (26), which is crucial for the success of pregnancy (25,31), T cell IL-4 production induced in response to the treatment with G-CSF of patients with unexplained recurrent miscarriages, could explain the increased live-birth rates in these patients. Of course in these two studies (29,30) the supplementation of rh G-CSF demonstrated the influence of G-CSF at endometrial level, it would be of great interest to investigate the role of this cytokine on oocyte and embryo growth and development.…”