Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells

Abstract

Dendritic cells (DC) are highly specialized antigen-presenting cells characterized by the ability to prime T-cell responses. Mesenchymal stem cells (MSC) are adult stromal progenitor cells displaying immunomodulatory activities including inhibition of DC maturation in vitro. However, the specific impact of MSC on DC functions, upon in vivo administration, has never been elucidated. Here we show that murine MSC impair Toll-like receptor-4 induced activation of DC resulting in the inhibition of cytokines secretion, down-regulation of molecules involved in the migration to the lymph nodes, antigen presentation to CD4 + T cells, and cross-presentation to CD8 + T cells. These effects are associated with the inhibition of phosphorylation of intracellular mitogen-activated protein kinases. Intravenous administration of MSC decreased the number of CCR7 and CD49dβ1 expressing CFSE-labeled DC in the draining lymph nodes and hindered local antigen priming of DO11.10 ovalbumin-specific CD4 + T cells. Upon labeling of DC with technetium-99m hexamethylpropylene amine oxime to follow their in vivo biodistribution, we demonstrated that intravenous injection of MSC blocks, almost instantaneously, the migration of subcutaneously administered ovalbumin-pulsed DC to the draining lymph nodes. These findings indicate that MSC significantly affect DC ability to prime T cells in vivo because of their inability to home to the draining lymph nodes and further confirm MSC potentiality as therapy for immune-mediated diseases.immunomodulation | tolerance S tromal progenitors of mesodermal cells, referred to as mesenchymal stem cells (MSC) or multipotent mesenchymal stromal cells, are a heterogeneous population of self-renewing and multipotent cells isolated from the bone marrow (BM) (1). MSC raised hopes for their clinical exploitation for tissue-repair strategies and increasing experimental evidence supports their use also for immune-mediated diseases (2). In fact, MSC display a striking capacity of modulating the immune response (3). Despite a large body of experimental studies addressing the in vitro effects of MSC on immune cells, little is known about the mechanisms of MSCmediated inhibition of the in vivo immune response. Dendritic cells (DC) are unique antigen-presenting cells (APCs) endowed with the ability of acquiring and processing antigens, up-regulating costimulatory molecules and therefore priming naive T cells. To present antigens to naive T cells, CCR7-expressing DC must migrate through lymphatic vessels from sites of inflammation to the closest draining lymph node (4). Activation of DC via Toll-like receptors (TLRs) up-regulates the expression of chemokine receptors involved in DC migration to the lymph nodes and enhances their in vivo mobilization properties (5). As a consequence, the total number of DC migrating in the draining lymph nodes deeply affects naive T-cell priming (6). Here we show that murine MSC inhibit in vitro DC effector properties, including antigen processing and presentation to T cells through the inhib...

Mesenchymal Stem Cells Shape Microglia Effector Functions Through the Release of CX3CL1

“…Interestingly, MSC can induce dendritic cells to acquire a tolerogenic phenotype in vitro and in vivo [45] and educate alternatively activated macrophages [46] which have been demonstrated to be essential players in CNS healing [47]. Recently, Zhou et al [48] demonstrated that MSC are able to inhibit LPS-stimulated microglia activation and the production of inflammatory factors through diffusible molecules and, within an inflammatory environment, can significantly increase the production of neurotrophic factors, possibly involved in tissue repair.…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…Injected MSCs also prevent the differentiation and maturation of monocytes into dendritic cells (DCs) in vivo (Ramasamy et al, 2007). Furthermore, MSCs block almost instantaneously the migration of CCR7-and α4β1-expressing DCs into draining lymph nodes to hinder local antigen presentation to CD4 + T cells and cross-presentation to CD8 + T cells (Chiesa et al, 2011). Recently, when transplanted into the lesion epicenter of rats with contusion SCI, MSCs migrated within the injured spinal cord without differentiating into glial or neuronal elements.…”

“…Interestingly, only small numbers (between 1 and 5%) of systemically injected MSCs and NPCs traffic over the inflamed CNS, whereas a rather significant accumulation of transplanted stem cells is observed at the level of the spleen and the draining lymph nodes (Bacigaluppi et al, 2008(Bacigaluppi et al, , 2009Capone et al, 2007;Chiesa et al, 2011;Gerdoni et al, 2007;Lee et al, 2008;Pluchino et al, 2009a,b;Sun et al, 2010). Here, stem cells extensively interact with the host immune system to inhibit the activation and proliferation of T cells (Gerdoni et al, 2007), the maturation of DCs (Pluchino et al, 2009b), or the emigration of spleen neutrophils toward the damaged brain (Lee et al, 2008).…”

The Sca1+ mesenchymal stromal subpopulation promotesdendritic cell commitment in the niche

“…Studies show that MSCs inhibit the initial differentiation of monocytes to DCs and induce mature DCs into a regulatory DCs population (Jiang et al, 2005). Researchers have shown that MSCs also inhibit T-cell proliferation (Chiesa et al, 2011). MSCs are heterogeneous cells whose subpopulation may impose opposite effects on DC commitment compared to general MSCs, however.…”

“…Mesenchymal stromal cells (MSCs) are the most important components in the niche (Frenette et al, 2013). Recently, Jiang et al (2005) reported that MSCs inhibited DC differentiation and maturation (Spaggiari et al, 2009;Zhang et al, 2009;Lai et al, 2010), as well as DC effector properties, including antigen processing and presentation to T cells (Chiesa et al, 2011).…”