Heat shock protein gp96 : modulates innate immune response at the materno-fetal interface

Heat shock protein (HSP) gp96 is expressed in the lumen of the endoplasmatic reticulum. Gp96-peptide complex "shuttle" antigenic peptides into MHC class I presentation pathway of antigen presenting cells (APCs). Recently, specific receptor (CD91) for gp96 has been identified on APCs. The presence of gp96 in the extracellular milieu alerts the APCs to physical damage of the surrounding cells. We have studied expression of gp96 at the materno-fetal interface to clarify the role of gp96 on the implantation site. We have examined the localization of the gp96 and its receptor CD91 by immunohistology in decidual tissue from women during the first trimester of normal pregnancy. Decidual cell isolation was accomplished by enzymatic digestion. Immunofluorescency was used to analyze the phenotype of CD83 and CD56+ cells upon stimulation with necrotic and apoptotic cells (K562). Proliferation rate of CD56+ was measured by CFSE proliferation assay. The highest expression of gp96 was detected on extravillous cytotrophoblast cells. CD91 molecule was expressed on the decidual adherent cells. We have found that CD91+ cells express HLA-DR, CD83 and CD56 molecules. After stimulation with necrotic cells and anti-gp96 we have obtained down-regulation of CD86, HLA-DR molecule on the decidual CD83 positive cells as well as inhibition of proliferation rate and down-regulation of perforin and CD69 expression of decidual CD56 positive cells. Heterogeneous expression of gp96 (being most intense on extravillous trophoblast cells) at the materno-fetal interface, suggests a regulatory role of this stress protein and its ability to mediate activation of APCs and NK cells in decidua.