EGF module-containing mucin-like hormone receptor 2 and its role in human immune privilege
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PURPOSE: In the mouse, the macrophage adhesion G protein-coupled receptor (ad-GPCR) molecule, F4/80, is required for the development of regulatory T cells in two models of tolerance, the eye and gut. Since F4/80 is not expressed in humans, the purpose of this research is to determine the human analog of F4/80. F4/80 belongs to a novel family of Epidermal growth factor-seven transmembrane (EGF-TM7) molecules, which include the EGF module-containing mucin-like hormone receptor (EMR) molecules. In the human, EMR1 has sequential homology with F4/80 and EMR2 has shown immune suppressing function in tumor cells. Thus, we investigate the possible suppressor role of the EMR family in human ocular tolerance. METHODS: Human peripheral blood mononuclear cells (huPBMC) were treated with porcine TGFβ2 and LPS or an antigenic stimulant for at least six hours to generate tolerogenic antigen presenting cells (APC). Cells were characterized by flow cytometric analysis for expression of CD14, CD40, PDL1, ILT3, and EMR2. Later, T regulatory cells were generated by incubating tolerogenic APCs with autologous huPBMC for five to seven days. Post culture, the T cells were stained and characterized for expression of CD4, CD25, and FoxP3. RESULTS: Post treatment of huPBMC with TGFβ2 and antigen, the resulting tolerogenic APCs expressed PDL1, ILT3, and EMR2. CD40 remained unchanged and CD14 was constitutively expressed. Post five to seven day culture, tolerogenic APCs treated with TGFβ2 increased the CD4+ CD25+ FoxP3+ lymphocyte populations. CONCLUSIONS: The upregulation of EMR2 on human tolerogenic APCs suggests that EMR2 may have a role in inducing tolerance in humans. Much like its mouse counterpart, F4/80, EMR2 is an adhesion molecule that may facilitate the induction of naïve T lymphocytes to regulatory T lymphocytes. Once the F4/80 analog is established for humans, novel therapies may be developed to interfere or encourage signaling in the treatment of tumors or immune inflammatory diseases, respectively.