The role of glycodelin as an immune-modulating agent at the feto-maternal interface

Glycodelin A is a progesterone-induced endometrial glycoprotein which has been amply documented to play a role in down-modulation of the maternal immune response to fetal allo-antigens and to be indispensable for the maintenance and progression of pregnancy. Earlier studies from our laboratory have focused on the effect of glycodelin on T cells, key regulators of both the antibody and cell-mediated arms of the acquired immune system. Glycodelin-induced apoptosis inactivated T cells occurs through a caspase-dependant intrinsic mitochondrial pathway. Interestingly, glycodelin inhibited the proliferation of B cells but did not induce apoptosis. More recently, we have studied the effect of glycodelin on the cells of the innate immune system, namely monocytes and NK cells. We have found that glycodelin induced apoptosis in monocytic cells before their differentiation to macrophages, via the mitochondrial pathway, but did not affect their phagocytic capacity after differentiation. Glycodelin induced apoptosis in NK cells but this activity was independent of caspases. In conclusion, glycodelin is observed to affect many cells of the immune system, although the nature of the effect and signaling mechanisms involved in each cell type may be distinct.

Glycodelin A triggers T cell apoptosis through a novel calcium-independent galactose-binding lectin activity

Glycodelin A (GdA) is one of the progesterone inducible endometrial factors that protect the fetal semiallograft from maternal immune rejection. The immumoregulatory effects of GdA are varied, with diverse effects on the fate and function of most immune cell types. Its effects on T cells are particularly relevant as it is capable of regulating T cell activation, differentiation, as well as apoptosis. We have previously reported that GdA triggers mitochondrial stress and apoptosis in activated T cells by a mechanism that is distinct and independent of its effects on T cell activation. In this study we describe the characterization of a cell surface receptor for GdA on T cells. Our results reveal a novel calcium-independent galactose-binding lectin activity of GdA, which is responsible for its apoptogenic function. This discovery adds GdA to a select group of soluble immunoregulatory lectins that operate within the feto-placental compartment, the only other members being the galectin family proteins. We also report for the first time that both CD4(+) and CD8(+) T cell subsets are equally susceptible to inhibition with GdA, mediated by its novel lectin activity. We demonstrate that GdA selectively recognizes complex-type N-linked glycans on T cell surface glycoproteins. and propose that the galectin-1 glycoprotein receptor CD7 maybe a novel target for GdA on T cells. This study, for the first time, links the lectin activity of GdA to its biological function.

Mapping the apoptosis inducing domain of an immunomodulatory protein: glycodelin A

Glycodelin A (GdA) is a dimeric glycoprotein synthesized by the human endometrium under progesterone regulation. Based on the high sequence similarity with beta-lactoglobulin, it is placed under the lipocalin superfamily. The protein is one of the local immunomodulators present at the feto-maternal interface which affects both the innate as well as the acquired arms of the immune system, thereby bringing about successful establishment and progression of pregnancy. Our previous studies revealed that the domain responsible for the immunosuppressive activity of glycodelin lies on its protein backbone and the glycans modulate the same. This study attempts to further delineate the apoptosis inducing region of GdA. Our results demonstrate that the stretch of amino acid sequence between Met24 to Leu105 is necessary and sufficient to inhibit proliferation of T cells and induce apoptosis in them. Further, within this region the key residues involved in harboring the activity were shown to be present between Asp52 and Ser65.