Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Abstract

SummaryThe mechanisms underlying the immunomodulatory effects of mesenchymal stem cells (MSCs) have been investigated under extreme conditions of strong T cell activation, which induces the rapid death of activated lymphocytes. The objective of this study was to investigate these mechanisms in the absence of additional polyclonal activation. In co-cultures of peripheral mononuclear blood cells with human MSCs (hereafter referred to as hMSCs), we observed a striking decrease in the level of CD8 expression on CD8+ cells, together with decreased expression of CD28 and CD44, and impaired production of IFN-gamma and Granzyme B. This effect was specific to hMSCs, because it was not observed with several other cell lines. Downregulation of CD8 expression required CD14+ monocytes to be in direct contact with the CD8+ cells, whereas the effects of hMSCs on the CD14+ cells were essentially mediated by soluble factors. The CD14+ monocytes exhibited a tolerogenic pattern when co-cultured with hMSCs, with a clear decrease in CD80 and CD86 co-stimulatory molecules, and an increase in the inhibitory receptors ILT-3 and ILT-4. CD8+ cells that were preconditioned by MSCs had similar effects on monocytes and were able to inhibit lymphocyte proliferation. Injection of hMSCs in humanized NSG mice showed similar trends, in particular decreased levels of CD44 and CD28 in human immune cells. Our study demonstrates a new immunomodulation mechanism of action of hMSCs through the modulation of CD8+ cells towards a non-cytotoxic and/or suppressive phenotype. This mechanism of action has to be taken into account in clinical trials, where it should be beneficial in grafts and autoimmune diseases, but potentially detrimental in malignant diseases.

Blood tolerogenic monocytes and low proportions of dendritic cell subpopulations are hallmarks of human tuberculosis

“…Such suppressive monocytes could also induce regulatory CD8 + T lymphocytes that could convert the potentially protective cytotoxic CD8 + T cells to suppressive CD8 + T lymphocytes . Finally, suppressive CD14 + monocytes are also characterized by a down regulation of the expression of HLA‐DR, CD80 and CD86 molecules, a phenotype previously reported for the monocytes from patients with aTB, and confirmed in our study for the CD86 expression.…”

Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism

“…The abilities of MSCs to indirectly inhibit B cell differentiation (via MSC release of interleukin‐1 receptor antagonist resulting in anti‐inflammatory macrophage [26]) and to downregulate CD8 T‐cell responses (via MSC soluble factors affecting CD14+ monocytes [47]) have also been highlighted. In the latter study, similar to our work, removal of CD14+ cells from PBMCs abrogated the effect of MSC‐soluble products on the T‐cell responses [47]. The potential for MSCs to mediate either pro‐ or anti‐inflammatory immune responses appears not to be restricted to effects on T cells or myeloid cells, because MSC have been reported to either up‐ or downregulate B cell responses, including their proliferation and differentiation [48–50].…”

The immunomodulatory function of mesenchymal stem cells: mode of action and pathways

“…Intravenous administration of MSCs shortly afterward led to impaired priming of antigen‐specific naive T cells, with significantly decreased cell numbers in the draining lymph nodes that were attributable to markedly reduced migration of DCs due, at least in part, to the significantly downregulated expression of CCR7 and CD49dβ1, which are involved in DC homing to lymphoid organs . Through their investigation on the effects of human adipose tissue–derived MSCs on CD8 + T cells in PBMCs, Hof‐Nahor et al . found that the observed downregulation of CD8 protein expression by T cells, not owing to reduced transcription, and their shift to a suppressive phenotype were mediated indirectly through MSC‐derived soluble factors acting to modulate CD14 + monocytes toward a suppressor phenotype .…”

“…Through their investigation on the effects of human adipose tissue–derived MSCs on CD8 + T cells in PBMCs, Hof‐Nahor et al . found that the observed downregulation of CD8 protein expression by T cells, not owing to reduced transcription, and their shift to a suppressive phenotype were mediated indirectly through MSC‐derived soluble factors acting to modulate CD14 + monocytes toward a suppressor phenotype . In this context, Chen et al .…”