Mesenchymal stromal cells and regulatory T cells: the Yin and Yang of peripheral tolerance?

Abstract

In recent years, mesenchymal stromal cells (MSCs) and regulatory T cells (Tregs) have both garnered significant interest from immunologists worldwide, not least because of the potential application of both cell types in the treatment of many chronic inflammatory and autoimmune diseases. Although both MSCs and Tregs can be considered immunosuppressive in their own right, the induction of Tregs by activated MSCs is now a well-publicised phenomenon; however, only recently have the mechanisms involved in this induction started to become clear. Indeed, it is becoming increasingly apparent that there exists a complex interplay between the two lineages leading to this potent inhibition of the host immune response. Cell contact, soluble mediators-including prostaglandin E(2) and transforming growth factor β-and indirect induction via manipulation of other antigen-presenting cells all appear to have vital roles in the interactions between MSCs and Tregs. Much still remains to be discovered before we have a full understanding of this important aspect of the immune response, but there have already been a multitude of clinical trials suggesting that MSC/Treg therapies could offer significant benefits in the treatment of both autoimmune disease and graft versus host disease. Although these therapies are still in their infancy, the synergy between MSCs and Tregs will undoubtedly yield future breakthroughs in the treatment of many debilitating conditions and usher in a new wave of targeted, cell-based therapeutics.

Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis

“…Several studies have demonstrated the ability of MSCs to polarize T cells toward a regulatory phenotype; this serves as an important mechanism by which MSCs dampen inflammation reactions and tissue damage. 25 Notably, we found for the first time that OE-MSCs possess a profound inhibitory capacity in suppressing effector T-cell proliferation. MSC-mediated immune modulation occurs mainly through paracrine effects by producing soluble factors, The CIA group had augmented fibrovascular synovial and periarticular proliferation (fp) and inflammatory cell infiltration (ici) levels.…”

Bone Marrow Mesenchymal Stromal Cells Isolated from Multiple Sclerosis Patients have Distinct Gene Expression Profile and Decreased Suppressive Function Compared with Healthy Counterparts

“…Secretion of TGF-b by MSCs has been implicated in the activation and expansion of Tregs (6). Indeed, lymphocytes obtained from healthy individuals stimulated with alloantigen in the presence of MSCs produce large amounts of IL-10.…”

“…Among the immunosuppressive and immunoregulatory functions, MSCs have the ability to inhibit i) T CD4 + cell proliferation; ii) proinflammatory Th1 and Th17 cytokine secretion, iii) cytotoxicity and proliferation of natural killer (NK) and T CD8 + cells, iv) differentiation of monocytes into dendritic cells, v) apoptosis and respiratory burst of neutrophils, and vi) B-cell proliferation and antibody production (30,52). In addition, MSCs induce generation and expansion of regulatory T-cells (6,(17)(18)(19)46). Several mechanisms have been shown to be responsible for the immunomodulatory properties of MSCs, and currently it is a consensus that soluble factors released by these cells play a key role in their suppressive and immunomodulatory activity (3,13).…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…Traditionally, secretion of IDO, TGF-β, and PGE2 by MSCs promotes Treg induction, expansion, and activation, respectively. In this sense, cell-to-cell contact also seems to be important [189]. In the in vivo scenario, though, adenosine shows up as another important molecule produced by MSCs and Tregs, which influence the function of the latter.…”

“…Curiously, though, the interaction between Tregs and MSCs has been poorly investigated so far, despite some pieces of evidence pointing at an important interplay between them, which could lead to potent inhibition of immune response. In fact, not only MSC influence Tregs directly, by inducing their formation and expansion, but also indirectly, by modulating antigen-presenting cells and inducing regulatory phenotypes [189].…”