Focal Localization of Placental Protein 14 Toward Sites of TCR Engagement

Rachmilewitz, Jacob; Borovsky, Zipora; Mishan-Eisenberg, Galit; Yaniv, Einat; Riely, Gregory J.; Tykocinski, Mark L.

doi:10.4049/jimmunol.168.6.2745

Cited by 16 publications

(15 citation statements)

References 20 publications

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“…We have reported that PP14 directly inhibits human T cells and accounts for the T cell inhibitory activity of AF (37). Our findings further suggested that PP14 targets early events during TCR signal transduction (37), facilitates the dephosphorylation of TCR-induced phosphoproteins, (38), and has the intriguing capacity to elevate TCR activation thresholds (39). This latter finding points to an unusual immunoregulatory mechanism for PP14 that is dis-tinct from that of other better characterized T cell suppressive factors (such as cyclosporin A).…”

supporting

confidence: 66%

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

Rachmilewitz¹,

Borovsky²,

Riely³

et al. 2003

Journal of Biological Chemistry

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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.

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supporting

confidence: 66%

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

Rachmilewitz¹,

Borovsky²,

Riely³

et al. 2003

Journal of Biological Chemistry

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“…In this way, PP14 has opposite effects to costimulation through CD28 (37). Other mechanistic clues lie in the dependence of the T cell inhibitory activity of PP14 on the surface phosphatase CD45 (7), suggesting that PP14 may somehow interfere with the transit of CD45 and perhaps other components in and out of APC:T cell contact sites (5).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the amplifying effects of costimulation, we have previously demonstrated that the immunomodulatory glycoprotein, placental protein 14 (PP14; 3 also known as glycodelin (4)), translocates to APC:T cell contact sites, where it decreases stability of TCR-induced phosphoproteins (5). This latter activity of PP14 fits in well with the antagonism between CD28-mediated costimulation and PP14-mediated inhibition (6) as well as with recent data indicating that the inhibitory activity of PP14 is mediated by the tyrosine phosphatase receptor, CD45 (7).…”

Section: N Aive Cd4mentioning

confidence: 99%

“…There are a growing number of features of PP14-mediated inhibition that we have documented to date. These include decreased duration of TCR-induced phosphorylated substrates (5), CD45 phosphatase dependence (7), and localization of PP14 to APC:T cell contact sites (5). Perhaps the most intriguing aspect of the T cell immunoregulatory function of PP14 is its rheostatic mechanism for T cell inhibition based on elevation of TCR activation thresholds (6), in contrast to costimulation through CD28, which functionally lowers T cell activation thresholds (37).…”

Section: Itkmentioning

confidence: 99%

“…Previously, we raised the possibility that PP14 may account, at least in part, for some of the interesting immunological features of pregnancy (5). One of these is the amelioration of certain cellmediated autoimmune diseases that occurs during pregnancy.…”

Section: Itkmentioning

confidence: 99%

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Differential Regulation of Th1/Th2 Cytokine Responses by Placental Protein 14

Mishan-Eisenberg¹,

Borovsky²,

Weber

et al. 2004

The Journal of Immunology

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The potency of TCR signaling during primary CD4+ T cell activation influences initial cytokine expression patterns and subsequent polarization toward either Th1 or Th2 subsets. In this study, we demonstrate that the T cell inhibitor placental protein 14 (PP14; glycodelin) preferentially inhibits Th1 cytokine responses and chemokine expression when present during ex vivo priming of CD4+ T cells. PP14 synergizes with exogenously added IL-4 in skewing T cell responses. Significantly, PP14 impairs the down-regulation of GATA-3 transcriptional regulator expression that normally accompanies T cell activation, which is a prerequisite for Th1 development. Taken together, these data document for the first time the ability of PP14 to skew Th responses.

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Serial Triggering Model

Rachmilewitz¹

Advances in Experimental Medicine and Biology

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T-cells recognize a foreign antigen when presented on antigen-presenting cells (APCs) in the context of a peptide bound to major histocompatibility complex (MHC). The recognition of an antigen takes place at the T-cell:APC contact site where an "immune synapse is formed and the multichain T-cell antigen receptor (TCR) is triggered. This initiates a signal transduction cascade that involves activation of tyrosine kinases, which in turn activate downstream events that elicit a diverse array of effector functions. T-cell activation requires a sustained signal that lasts for several hours. However, TCR affinity to its antigen is low and activation ofTCR induces only a brief spike of intracellular signals. The serial triggering model resolves these seemingly paradoxical requirements for T-cell activation. The model states that sustained signaling is accomplished by the concerted action of multiple T-cell receptors that are sequentially engaged with and triggered by the peptide:MHC complex. In this chapter, we review the serial triggering model and two other models that expand this modeL These models describe kinetic aspects of T-cell activation such as the pivotal question of how the T-cell "counts" the number of serially triggered receptors over time and how it determines that a threshold level has been reached for the activation ofT-cell response.

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Focal Localization of Placental Protein 14 Toward Sites of TCR Engagement

Cited by 16 publications

References 20 publications

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

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

Differential Regulation of Th1/Th2 Cytokine Responses by Placental Protein 14

Serial Triggering Model

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