Negative Regulation of T Cell Activation by Placental Protein 14 Is Mediated by the Tyrosine Phosphatase Receptor CD45

Abstract

CD45 is the major protein tyrosine phosphatase receptor on T cell surfaces that functions as both a positive and a negative regulator of T cell receptor (TCR) signaling. Although CD45 is required for the activation of TCR-associated Src family kinases, it also dephosphorylates phosphoproteins involved in the TCR-signaling cascade. This study links CD45 to the inhibitory activity of placental protein 14 (PP14), a major soluble protein of pregnancy that is now known to be a direct modulator of T cells and to function by desensitizing TCR signaling. PP14 and CD45 co-capped with each other, pointing to a physical linkage between the two. Interestingly, however, the binding of PP14 to T cell surfaces was not restricted to CD45 alone, with evidence showing that PP14 binds to other surface molecules in a carbohydratedependent fashion. Notwithstanding the broader molecular binding potential of PP14, its interaction with CD45 appeared to have special functional significance. Using transfected derivatives of the HPB.ALL mutant T cell line that differ in CD45 expression, we established that the inhibitory effects of PP14 are dependent upon the expression of intact CD45 on T cell surfaces. Based upon these findings, we propose a new immunoregulatory model for PP14, wherein one of its surface molecular targets, CD45, mediates its T cell inhibitory activity, accounting for the intriguing capacity of PP14 to elevate TCR activation thresholds and thereby down-regulate T cell activation.

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

“…PP14, a glycoprotein overexpressed by dNKs (4) that shares immunosuppressive properties with gal1, is a candidate for such an interaction. Like gal1, PP14 also induces T cell apoptosis (32), colocalizes with CD45 on the cells to which it binds (33), and reacts with N-acetyllactosamines (34). Interestingly, PP14 is also expressed by glandular epithelium around which apoptotic T cells are seen, and has poly-N-acetyllactosamine moieties (35) to which gal1 could potentially bind.…”

Glycodelin in reproductive endocrinology and hormone-related cancer

“…Glycodelin appears to desensitise T-cell receptor (TCR) signalling by its association with the tyrosine phosphatase receptor, CD45 (53). Other mechanisms may also be involved because glycodelin-A is inhibitory to T-cells upon phorbol ester and ionophore stimulation that bypass the TCR-proximal signalling events (54).…”

“…Suppresses lymphocyte proliferation (56) Induces tolerogenic phenotype in monocyte-derived dendritic cells (57) Inhibits T cell activity/proliferation, induces apoptosis (53,58,59) Inhibits B cell activity/proliferation (60) Induces apoptosis in monocytes (64) produced in CHO cells (65) and from the fact that the major complex type N-glycans in glycodelin produced in CHO cells are devoid of the typical lacdiNAc glycans present in glycodelin-A (66). Accessibility to the apoptotic region of glycodelin may modulate apoptotic activity either by masking or unmasking the functional region in the glycodelin molecule (61).…”

Relation of Time of Introduction of Cow Milk Protein to an Infant and Risk of Type-1 Diabetes Mellitus

“…25,26 It is a major soluable protein of pregnancy and is known to directly modulate T cells. 27,28 It is a 28 kDa glycoprotein particularly expressed in steroid-responsive tissues of the female reproductive tract; the endometrium in response to progesterone. There is a large concentration in amnionic fluid which is thought to be a nutritive protein for the fetus in early pregnancy.…”