Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6—STAT3 signaling pathway

Abstract

The expression of Ig-like transcript (ILT) inhibitory receptors is a characteristic of tolerogenic dendritic cells (DCs). However, the mechanisms of modulation of DCs via ILT receptors remain poorly defined. HLA-G is a preferential ligand for several ILTs. Recently, we demonstrated that triggering of ILT4 by HLA-G1 inhibits maturation of human monocyte-derived conventional DCs and murine DCs from ILT4 transgenic mice, resulting in diminished expression of MHC class II molecules, CD80 and CD86 costimulatory molecules, and prolongation of skin allograft survival. Different isoforms of HLA-G have diverse effects on the efficiency to induce ILT-mediated signaling. In this work, we show that HLA-G1 tetrameric complex and HLA-G5 dimer, but not HLA-G5 monomer, induce strong ILT-mediated signaling. We determined that the arrest of maturation of ILT4-positive DCs by HLA-G ligands involves the IL-6 signaling pathway and STAT3 activation. Ligation of ILT4 with HLA-G on DCs results in recruitment of SHP-1 and SHP-2 protein tyrosine phosphatases. We propose a model where SHP-2 and the IL-6–STAT3 signaling pathway play critical roles in the modulation of DC differentiation by ILT4 and HLA-G.

Embryonic Trophoblasts Induce Decidual Regulatory T Cell Differentiation and Maternal–Fetal Tolerance through Thymic Stromal Lymphopoietin Instructing Dendritic Cells

“…HLA-G was described as a key physiological mediator of maternal-fetal tolerance (38)(39)(40)(41). HLA-G inhibits multiple immune cell functions, including cytolytic functions of uterine and peripheral blood NK cells, Ag-specific cytolytic functions of cytotoxic T lymphocytes, allo-responsiveness of CD4 influence induction of DC tolerance (44). HLA-G-expressing DC-10 and CD4 + T cells accumulate in human deciduas during pregnancy (45).…”

Generation of functional monocyte-derived fast dendritic cells suitable for clinical application in the absence of interleukin-6

“…Recently, it was also reported that several factors, such as IL-6, released by solid and liquid tumours affecting the maturation pathway of DCs (Liang et al 2008;Orsini et al 2003;Ratta et al 2002). Pancreatic cancer patient sera containing high levels of IL-6 significantly blocked the maturation of Mo-derived CD14 -CD1a ?…”

“…and CD8 ? T cells allostimulatory activity (Liang et al 2008). In addition, a functional defect in DCs from peripheral blood of myeloma and chronic lymphocytic leukaemia patients was partially due to an overproduction of IL-6 (Orsini et al 2003;Ratta et al 2002).…”

“…In addition, a functional defect in DCs from peripheral blood of myeloma and chronic lymphocytic leukaemia patients was partially due to an overproduction of IL-6 (Orsini et al 2003;Ratta et al 2002). The maintenance of tolerogenic DCs, characterized by secreting lower IL-12 and higher IL-10 as well as inability to activate antigen-specific T cells, was increased in the presence of IL-6 (Bellone et al 2006;Liang et al 2008). IL-6 clearly decreased the lipopolysaccharide-induced expression of MHC-class II, CD40, 80, 86 and IL-12 (p40/p70) on DCs (Park et al 2004).…”

Regulation of T‐cell immunity by leucocyte immunoglobulin‐like receptors: innate immune receptors for self on antigen‐presenting cells

“…LILRB2, but not LILRB1, recognizes HLA-G free heavy chains, 35,36 increasing its inhibitory effects on costimulation and T-cell responses. 37 Ectopic expression of HLA-G itself is sufficient to induce the up-regulation of inhibitory LILR, 38 and expression of both HLA-G and inhibitory LILR is up-regulated through the action of IL-10. 25,26,39,40 Ectopic expression of HLA-G as a high-affinity ligand for inhibitory LILR is likely to be an important factor in determining clinical outcomes in transplant tolerance, infection and cancer.…”