The induction of APC with a distinct tolerogenic phenotype via contact-dependent STAT3 activation.

Background: Activation of the signal transducer and activator of transcription 3 (STAT3) within antigen presenting cells (APCs) is linked to abnormal APCs differentiation and function. We have previously shown that STAT3 is activated within APC by a novel contact-dependent mechanism, which plays a key role in mediating the immunomodulatory effects of hMSC. In order to better understand the underlying mechanisms that control APC maturation in a contact dependent manner, we extended our observation to tumor cells.

Contact-dependent induction of regulatory antigen-presenting cells by human mesenchymal stem cells is mediated via STAT3 signaling.

Objective: Mesenchymal stem cells (MSCs) are multipotent cells that are capable of differentiating into multilineages of the mesenchyme. MSCs were shown to have immune-modulating properties in vitro and were successfully used in vivo for controlling graft-versus-host disease, skin rejection, and modulation of inflammation. Our previous study suggested that human MSCs (hMSCs) block antigen-presenting cell (APC) maturation in a contact-dependent manner as well as induce the expression of the anti-inflammatory cytokine, interleukin-10 (IL-10).

alpha2,6-Sialylation promotes binding of placental protein 14 via its Ca2+-dependent lectin activity: insights into differential effects on CD45RO and CD45RA T cells.

Placental protein 14 (PP14; glycodelin) is a pregnancy-associated immunoregulatory protein that is known to inhibit T cells via T-cell receptor desensitization. The recent demonstration of PP14 as lectin has provided insight into how it may mediate its CD45 glycoprotein-dependent T-cell inhibition. In this study, we have investigated PP14's lectin-binding properties in detail.

Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.

Infusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses.

Differential regulation of Th1/Th2 cytokine responses by placental protein 14.

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.

Placental protein 14 regulates selective B cell responses.

Placental protein 14 (PP14) is a glycoprotein of the lipocalin family that acts as a negative regulator in T cell receptor-mediated activation. In this study, we investigated PP14s potential role in regulating B cell activation. While PP14-inhibited B cell proliferation, IgM secretion and the surface expression of MHC class II, the expression of other surface molecules, such as CD69 and CD86, were unaffected.

Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45.

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.

Serial triggering of T cell receptors results in incremental accumulation of signaling intermediates.

Triggering of the T cell receptor (TCR) leads to the production of intracellular intermediates with half-life of a few minutes. Signaling kinetics of events originating from serial TCR triggering and its relation to antigen dose was investigated. In this study we documented incremental accumulation of short-lived intermediates of the extracellular signal-regulated kinase (ERK) family, produced during successive TCR triggering.

Focal localization of placental protein 14 toward sites of TCR engagement.

TCR signal transduction is amplified by the dynamic accumulation of accessory molecules at APC-T cell contact sites, along with the simultaneous exclusion from these sites of negative regulators, such as certain tyrosine phosphatases and large glycosylated proteins. However, given the general nature of the cytoskeleton-driven clustering mechanism underlying molecular segregation events at the APC-T cell interaction site, the possibility exists that negative regulators might similarly be segregated at these sites. Using fluorescence microscopy, we have demonstrated that placental protein 14 (PP14), a direct T cell inhibitor, focuses toward APC-T cell contact sites in conjunction with conjugate formation.