Placental protein 14 regulates selective B cell responses
Introduction
Placental protein 14 (PP14)1 also known as progesterone-associated endometrial protein [1] and glycodelin [2] is a member of the lipocalin structural family [3]. PP14, a 28-kDa glycoprotein, is secreted by the endometrial decidua of early pregnancy, constituting up to 10% of total decidual protein in the first trimester, and occurs in remarkably high concentrations in amniotic fluid (AF) during the first half of pregnancy (125 mg/L; of decidual origin) [4], [5]. Significant concentrations of PP14 are also present in tumors of reproductive organs (as well as in the plasma of patients with these tumors) [6], [7], in plasma during early pregnancy [5], and in male seminal fluid [8]. PP14 has also been identified outside of the reproductive system, within cells of the megakaryocytic lineage, including platelets [9]. One unique feature of amniotic PP14 is its high mannose-, hybrid-, and complex-type biantennary oligosaccharides, including structures with fucosylated or sialylated N,N′-diacetyllactosediamine (GalNAcbeta1-4GlcNAc) sequences, which are rare in other human glycoproteins [2].
PP14 has been shown to inhibit sperm–zona interaction [10], [11], and to promote angiogenesis, possibly by promoting VEGF expression, with it being present in endothelial cells of umbilical cord and in blood vessels of tumors [12]. Additionally, PP14 has been shown to have immunoinhibitory capacity in that it inhibits two-way mixed-lymphocyte reactions, inhibits proliferation and cytokine production [13], [14], [15], [16], [17] and inhibits NK activity [18]. Furthermore, recent studies have demonstrated that PP14 inhibits monocyte trafficking [19] and induce apoptosis in T cells [20]. These immunoinhibitory functions attributed to PP14 may explain, at least in part, the correlation between the serum levels of PP14 and the establishment and progression of normal pregnancy [21], [22], [23], and it is thus tempting to speculate that PP14 may contribute to the maternal immunotolerance to the semiallogeneic embryo.
In spite of the growing literature on the multifunctional role of PP14, little is known on the cells targeted by PP14 and its mode of action. We have previously reported that PP14 directly inhibits human T cells and accounts for the T cell inhibitory activity of AF [24]. Our findings further suggested that PP14 targets early events during TCR signal transduction [24] leading to decreased stability of TCR-induced phosphoproteins [25], and in so doing, operates via a unique immunoregulatory mechanism, “rheostatically” elevating T cell receptor activation thresholds [26]. We have further established that PP14 translocates to antigen-presenting cell (APC):T cell contact sites and its inhibitory activity depends upon its access to the triggered TCR.
Considering the possibility that CD45 might explain, at least in part, PP14s effects on the dephosphorylation of TCR-induced phosphoproteins and TCR activation thresholds, we proposed a connection between PP14 and CD45. Our recent data [27] establish the existence of both physical and functional links between the two; with a clear demonstration that PP14s inhibitory effect is dependent on the surface expression of the extracellular and/or transmembrane domains of the tyrosine phosphatase receptor, CD45. However, PP14 does not interact with a single discrete surface receptor on T cells, but rather with multiple surface molecules in a carbohydrate-dependent fashion, among them, the abundant CD45 molecule. This fundamental insight into PP14s binding potentials casts its immunoregulatory activities in a new light, with similarities to galectin-1, an animal lectin that also binds to CD45.
Although, the TCR and the B cell Ag receptor (BCR—membrane Ig (mIg)) recognize fundamentally distinct forms of antigens, the signal transduction events that result from the interaction of their antigen receptors with antigen are quite similar. Protein–tyrosine phosphorylation is involved in the initiation of cellular responses by antigen receptors, but neither TCR nor the BCR has intrinsic PTK activity. Cross-linking of the receptors after ligand-binding triggers the signaling cascade by association with subunits that contain in their cytoplasmic domains immunoreceptor tyrosine-based activation motifs (ITAMs), and the phosphorylation of ITAM tyrosines by a Src family kinase. The activation of the Src family kinase is achieved by the tyrosine phosphatase receptor, CD45, which is essential for both TCR and BCR signal transduction [28], [29], [30]. In addition to the antigen receptors, other receptors contribute to cell activation, such as CD19 and CD28, which function by amplifying signals received by the antigen receptors, thereby lowering their threshold for activation, in B and T cells, respectively.
These striking similarities between the activation pathways of the T and B cell receptors, combined with our knowledge on PP14s effect on TCR signaling, provide the rationale for studying B cells as potential targets for PP14. We tested this assumption by assessing PP14s effect on purified human B cell activation. The data presented here indicate that PP14 inhibits several BCR-induced B cell responses while not affecting others. The characteristic of PP14s B cell inhibitory activity was distinctly different from that previously documented for T cells and reminiscent of that achieved by triggering CD19 by specific antibodies.
Section snippets
Cells
Cells were purified from the venous blood of healthy donors. B cells isolated either by positive selection using anti-CD19 microbeads with magnetic cell isolation system (Miltenyi Biotec, Germany), or by negative selection using RosetteSep human B cell enrichment cocktail (StemCell Technologies, Vancouver, Canada). All the experiments were performed with B cells isolated by the two methods with similar results. Monocytes were isolated from mononuclear cell populations by adherence to plastic as
Results
Previously, we demonstrated that PP14 inhibits TCR-induced T cell activation. Based on the similarities between TCR and BCR activation pathways, we hypothesized that PP14 may similarly affect BCR-induced B cell activation. To examine for such a possibility, purified human B cells were stimulated with varying concentrations of anti-IgM antibody in the presence or absence of either AF, used as a natural source for PP14, or recombinant PP14·Fcγ1 fusion protein. Ligation of IgM by either whole
Discussion
The present study builds upon previous studies indicating that PP14 exhibits immunosuppressive properties and suggesting that PP14 may play a role in the establishment and progression of pregnancy. Specifically, our previous studies demonstrated that PP14 directly inhibit T cell activation [24]. The data presented here clearly demonstrate that PP14 has a negative role in B cell antigen receptor-mediated activation of human B cells. However, while significant inhibition of B cell proliferation,
Acknowledgments
We thank M.L. Tykocinski for helpful discussion and critical reading of the manuscript. This study was supported by the Greensboro Community Foundation.
References (40)
- et al.
Structural analysis of the oligosaccharides derived from glycodelin, a human glycoprotein with potent immunosuppressive and contraceptive activities
J. Biol. Chem.
(1995) - et al.
Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of human spermatozoa to bind to the human zona pellucida
Fertil. Steril.
(1995) - et al.
Gender-specific glycosylation of human glycodelin affects its contraceptive activity
J. Biol. Chem.
(1996) - et al.
Identification of placental protein 14 as an immunosuppressive factor in human reproduction
Lancet
(1987) - et al.
Suppression of in vitro lymphocyte reactivity to phytohemagglutinin by placental protein 14
J. Reprod. Immunol.
(1988) - et al.
Purification and characterization of an immunomodulatory endometrial protein, glycodelin
J. Biol. Chem.
(2001) - et al.
Placental protein 14 induces apoptosis in T-cells but not in monocytes
J. Biol. Chem.
(2001) - et al.
Habitual abortion is accompanied by low serum levels of placental protein 14 in the luteal phase of the fertile cycle
Fertil. Steril.
(1995) - et al.
Placental protein 14 levels in uterine flushing and plasma of women with unexplained infertility
Fertil. Steril.
(1993) - et al.
Placental protein 14 functions as a direct T cell inhibitor
Cell Immunol.
(1999)
A rheostatic mechanism for T-cell inhibition based on elevation of activation thresholds
Blood
Evidence that the leukocyte-common antigen is required for antigen-induced T lymphocyte proliferation
Cell
CD22, a B cell-specific immunoglobulin superfamily member, is a sialic acid-binding lectin
J. Biol. Chem.
Natural ligands of the B cell adhesion molecule CD22 beta carry N-linked oligosaccharides with alpha-2,6-linked sialic acids that are required for recognition
J. Biol. Chem.
HinfI polymorphism in the human progesterone associated endometrial protein (PAEP) gene
Nucleic Acids Res.
The lipocalin protein family: structure and function
Biochem. J.
New soluble placental tissue proteins: their isolation, characterization, localization and quantification
Placenta Suppl.
Distribution of placental protein 14 in tissues and body fluids during pregnancy
Br. J. Obstet. Gynaecol.
Expression of glycodelin in human breast and breast cancer
Int. J. Cancer
Increased glycodelin levels in gynecological malignancies
Int. J. Gynecol. Cancer
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