Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells

TLDR

Bone marrow mesenchymal stem cells are known for potent immunosuppressive effects, yet the underlying mechanisms remain poorly understood and are thought to reflect a primitive stem cell function. The study aims to show that adult dermal fibroblasts can modulate T‑cell responses, highlighting their potential as an alternative immunoregulatory cell therapy. Fibroblast‑mediated suppression relies on soluble factors that require IFN‑γ from activated T cells, which induces IDO and accelerated tryptophan metabolism to inhibit T‑cell proliferation. Dermal fibroblasts inhibit allogeneic T‑cell activation, the effect is reversible and transient exposure reprograms T cells toward Th2 cytokine production, ameliorates graft‑vs‑host disease in a human model, and their clonogenicity indicates suppression is not due to rare MSC, supporting fibroblasts as a general stromal immunosuppressive source.

Abstract

Abstract Bone marrow mesenchymal stem cells (MSC) have potent immunosuppressive properties and have been advocated for therapeutic use in humans. The nature of their suppressive capacity is poorly understood but is said to be a primitive stem cell function. Demonstration that adult stromal cells such as fibroblasts (Fb) can modulate T cells would have important implications for immunoregulation and cellular therapy. In this report, we show that dermal Fb inhibit allogeneic T cell activation by autologously derived cutaneous APCs and other stimulators. Fb mediate suppression through soluble factors, but this is critically dependent on IFN-γ from activated T cells. IFN-γ induces IDO in Fb, and accelerated tryptophan metabolism is at least partly responsible for suppression of T cell proliferation. T cell suppression is reversible, and transient exposure to Fb during activation reprograms T cells, increasing IL-4 and IL-10 secretion upon restimulation. Increased Th2 polarization by stromal cells is associated with amelioration of pathological changes in a human model of graft-vs-host disease. Dermal Fb are highly clonogenic in vitro, suggesting that Fb-mediated immunosuppression is not due to outgrowth of rare MSC, although dermal Fb remain difficult to distinguish from MSC by phenotype or transdifferentiation capacity. These results suggest that immunosuppression is a general property of stromal cells and that dermal Fb may provide an alternative and accessible source of cellular therapy.