Activated human mesenchymal stromal cells process and present islet peptides inducing adaptive immune regulation of islet autoimmunity

Background: Mesenchymal stromal cells (MSCs) are inherently immunomodulatory, in particular when activated. We tested whether activated MSCs qualify for the induction of islet antigen specific immune regulation. Methods: Bone marrow derived human MSCs were activated by interferon-g (IFNg) and analyzed for immune regulatory features including phenotype, immunosuppressive capacity and metabolic activity. To assess whether adaptive immune responses can be regulated, MSCs were pulsed with a diabetes associated antigen (GAD65) to assess uptake and presentation of autoantigen to islet antigen-specific T-cell clones. Results: We confirmed that inflammatory activation of MSCs increased HLA class II, PD-L1, and intracellular IDO expression, as well as immunosuppressive capacity, whereas no effect was seen on co-stimulatory molecules. Activated MSCs remained locked in their metabolic phenotype. MSCs were able to uptake and process protein. Activated MSCs pulsed with GAD65 peptide inhibited proliferation of activated proinflammatory GAD65-specific T-cells, while HLA class II expression did not induce alloreactivity. Conditioning of GAD65-specific T-cells by activated MSCs pulsed with GAD65 peptide inhibited T-cell proliferation upon subsequent activation by GAD65-pulsed dendritic cells, even after removal of the MSCs. Conclusion: Activation of MSCs with inflammatory stimuli turns these cells into suppressive antigen-presenting cells, capable of mediating adaptive regulation of proinflammatory islet-specific T-cells, rather than increasing inflammation.