The Induction of APC with a Distinct Tolerogenic Phenotype via Contact-Dependent STAT3 Activation

Abstract

BackgroundActivation 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. Tumors were shown to secrete a variety of tumor-derived factors that activate STAT3 within infiltrating APCs. We now tested whether tumor cells can activate STAT3 within APC using the contact-dependent mechanism, in addition to soluble factors, and compared these two STAT3 activating pathways.Principal FindingsWe demonstrate that in addition to tumor-derived secreted factors tumor cells activate STAT3 by a mechanism that is based on cell-cell interaction. We further demonstrate that these two STAT3 activating mechanisms differ in their JAK usage and their susceptibility to JSI-124 inhibition thereby representing two distinct pathways. Significantly, although both pathways activate STAT3, they modulate DCs maturation in a different manner that results in disparate phenotypic outcomes. Whereas the soluble-dependent pathway results in an immature phenotype, the contact-dependent pathway results in an apparently mature phenotype. Albeit their mature-like phenotype these latter cells express the tolerogenic markers ILT3 and ILT4 and possess T cell inhibitory activity.SignificanceThis data suggests that, in at least certain cellular microenvironments, cell:cell interactions represent a novel way to activate STAT3 signaling, uncouple APC activation events and consequently regulate immunity and tolerance. Significantly, we have now demonstrated that this contact-dependent signaling pathway differs from that mediated by soluble factors and cytokines, inducing disparate phenotypic outcome, suggesting these two mechanisms have different and possibly complementary biological functions.

Hepatic Stellate Cells Undermine the Allostimulatory Function of Liver Myeloid Dendritic Cells via STAT3-Dependent Induction of IDO

“…In support of this, we found previously that the majority of active STAT3 was expressed in CD80 + or CD86 + liver mDCs (19). Earlier studies have shown that, in a tumor-specific environment, myeloid APCs mature in a contact-dependent manner via STAT3 activation (79, 80). Interestingly, STAT3 activation was also associated with increased IDO expression in HSC-conditioned liver mDCs.…”

Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions

“…PNG ILT3 1 ILT4 1 monocytes coexpressed high levels of HLA-DR, suggesting that cells with potential inhibitory function were those that had been activated in utero. Of interest, tolerogenic APCs are known to exist in a range of maturation states, 33 with ILT3 and ILT4 expression subject to modulation by infections 34 and, in neonates, by certain prenatal exposures. 35 Furthermore, APCs from PNG compared with Australian newborns overexpressed CD80 relative to CD86, which has been associated with promotion of T H 1 rather than T H 2 responses.…”

Novel CD47: SIRPα Dependent Mechanism for the Activation of STAT3 in Antigen-Presenting Cell

“…Interestingly, we have further extended this observation to tumor cells and suggested that in the case of tumor-mediated APC modulation, there are two parallel mechanisms for the activation of STAT3, soluble cytokines versus cell:cell contact. In aggregate, we have identified a novel, contact-dependent mechanism for STAT3 activation by a previously unknown JAK2-dependent signaling pathway that precedes IL-10 secretion and is distinct from the well-established cytokine-mediated pathway [9].…”