Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2

Abstract

T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients.

The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

“…In this study, PGE 2 secretion by MSC was required to increase IL‐10 production by monocytes/macrophages; however, the generation of PGE 2 by MSC in this case was dependent upon TNF‐α and iNOS signalling from monocytes/macrophages . In the human context it has been shown that human BM‐MAPC require priming by monocyte‐derived IL‐1β to produce PGE 2 (Table ). The importance of IL‐1 signalling is supported by the fact that human BM‐MSC require the IL‐1 signalling pathway in order to produce PGE 2 and TSG‐6 .…”

The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma

“…In melanoma and other cancers, the proinflammatory enzyme COX2 and its downstream metabolic pathway product, prostaglandin E2 (PGE2), are reported to enhance carcinogenesis and tumor progression and to support immunosuppression (8,9). PGE2 produced by tumor cells and/or their surrounding stromal cells induces immunosuppression through several mechanisms, including downregulating antitumor T helper 1 cytokines and upregulating immunosuppressive TH2 cytokines; inhibiting CD8 þ T-cell proliferation and activity, which suppresses the antitumor activity of natural killer cells and stimulates the expansion of regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSC); and inhibiting CD8 þ T-cell antitumor functions by impairing the ability of tumor cells to directly present tumor antigens, which inhibits dendritic cell differentiation and switches the function of dendritic cells from induction of immunity to T-cell tolerance (10)(11)(12)(13)(14)(15)(16)(17). In addition, tumor-derived COX activity in melanoma is a crucial suppressor of type I IFN-and T cellmediated tumor removal and the inducer of an inflammatory signature associated with cancer progression (18,19).…”

Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells

“…Previous findings demonstrated the need for MAPC to interact with monocytes in order to suppress homeostatic proliferation of T cells [60]. This effect was attributed to IL-1 β -dependent secretion of PGE2 by hMAPC.…”