Abstract
BackgroundFeline adipose-derived mesenchymal stem cells (ASCs) have been successfully used in clinical trials for the treatment of immune-mediated diseases with T cell dysregulation. However, the immunomodulatory pathways utilized by feline ASCs to suppress T cell activation have not been fully determined. We investigated the mechanisms used by feline ASCs to inhibit T cell proliferation, including the soluble factors and the cell-cell contact ligands responsible for ASC-T cell interaction.MethodsThe immunomodulatory activity of feline ASCs was evaluated via cell cycle analysis and in vitro mixed leukocyte reaction using specific immunomodulatory inhibitors. Cell-cell interactions were assessed with static adhesion assays, also with inhibitors.ResultsFeline ASCs decrease T cell proliferation by causing cell cycle arrest in G0–G1. Blocking prostaglandin (PGE2), but not IDO, partially restored lymphocyte proliferation. Although PDL-1 and CD137L are both expressed on activated feline ASCs, only the interaction of intercellular adhesion molecule 1 (ICAM-1, CD54) with its ligand, lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18), was responsible for ASC-T cell adhesion. Blocking this interaction reduced cell-cell adhesion and mediator (IFN-γ) secretion and signaling.ConclusionsFeline ASCs utilize PGE2 and ICAM-1/LFA-1 ligand interaction to inhibit T cell proliferation with a resultant cell cycle arrest in G0–G1. These data further elucidate the mechanisms by which feline ASCs interact with T cells, help define appropriate T cell-mediated disease targets in cats that may be amenable to ASC therapy, and may also inform potential translational models for human diseases.
Highlights
Feline adipose-derived mesenchymal stem cells (ASCs) have been successfully used in clinical trials for the treatment of immune-mediated diseases with T cell dysregulation
We previously hypothesized that feline ASCs could be licensed by Interferon gamma (IFN-γ) and this signaling may be critical for the long-term reprograming of CD8+ regulatory T lymphocytes [25,26,27]
As ASCs inhibit lymphocyte proliferation regardless of cell-cell contact, high IFN-γ concentration can be used as a surrogate marker of contact-mediated T cell inhibition and the reduction of IFN-γ secretion can be used as a marker of effective blockade of this pathway
Summary
Feline adipose-derived mesenchymal stem cells (ASCs) have been successfully used in clinical trials for the treatment of immune-mediated diseases with T cell dysregulation. We investigated the mechanisms used by feline ASCs to inhibit T cell proliferation, including the soluble factors and the cell-cell contact ligands responsible for ASC-T cell interaction. Mesenchymal stem cells (MSCs) are a heterogeneous, multipotent stromal cell population, capable of proliferating in vitro as plastic-adherent cells with fibroblast-like morphology and differentiating into bone, cartilage, and adipose cells [1]. Aside from their regenerative properties, MSCs possess immunomodulatory properties and have been used extensively to treat a wide variety of immune-mediated diseases, both in human and veterinary. In contrast to other species, including humans, dogs, and horses, feline ASCs inhibit lymphocyte proliferation in the context of significantly increased concentration of IFN-γ [8, 12, 13]
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