Abstract
Mesenchymal stem cells (MSCs) can modulate lymphocyte proliferation and function. One of the immunomodulatory functions of MSCs involves CD4+CD25+FoxP3+ regulatory T cells (Tregs), which negatively regulate inflammatory responses. MSC-mediated Treg induction is supposed to be regulated by mechanisms requiring both soluble and cell contact-dependent factors. Although the involvement of soluble factors has been revealed, the contact-dependent mechanisms in MSC-mediated Treg induction remain unclear. We attempted to identify molecule(s) other than secreted factors that are responsible for MSC-mediated Treg induction and to uncover the underlying mechanisms. Under in vitro Treg-inducing conditions, ICOSL expression in MSCs coincided with Treg induction in co-cultures of MSCs with CD4+ T cells. When cultured in a transwell plate, MSCs failed to induce Tregs. Neutralization or knockdown of ICOSL significantly reduced Tregs and their IL-10 release. ICOSL overexpression in MSCs promoted induction of functional Tregs. ICOSL-ICOS signaling promoted Treg differentiation from CD4+ T cells through activation of the phosphoinositide 3-kinase-Akt pathway. MSCs primed with Interleukin-1β significantly induced Tregs through ICOSL upregulation. We demonstrated that the Treg-inducing activity of MSCs is proportionate to their basal ICOSL expression. This study provides evidence that ICOSL expression in human MSCs plays an important role in contact-dependent regulation of MSC-mediated Treg induction.
Highlights
We examined the functional role of ICOS ligand (ICOSL) in Mesenchymal stem cells (MSCs)-mediated induction of CD4+CD25+FoxP3+ Tregs and revealed the underlying molecular mechanism
We reported drastic ICOSL induction in human MSCs stimulated with inflammatory cytokines but its functional role with respect to stem cell properties was not investigated[16]
ICOSL-expressing melanoma cells were reported to stimulate Treg induction, prompting us to question whether ICOSL in MSCs promotes Treg induction or conversion[15]
Summary
They showed that prostaglandin E2 (PGE2) and transforming growth factor-β1 (TGF-β1) play important roles in MSC-mediated induction of CD4+CD25+FoxP3+ Tregs[20] They demonstrated a reliable result for the involvement of a cell contact-dependent mechanism in Treg induction. They did not elucidate the molecular identity of the direct contact between MSCs and T cells for Treg induction, suggesting that other unknown molecular regulator(s) might be associated with the contact-dependent mechanism underlying this event. Based on these findings, we hypothesized that ICOSL expressed in MSCs may play a critical role in MSC-mediated Treg induction, by signaling via ICOS to promote Treg differentiation. We investigated the priming effect of interleukin-1β(IL-1β)on ICOSL upregulation to enhance the functional activity of MSCs for Treg induction
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