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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00694

Activated mesenchymal stromal cells process and present antigens regulating adaptive immunity

  • 1City of Hope National Medical Center, United States
  • 2Leiden University Medical Center, Netherlands
  • 3Federal University of Minas Gerais, Brazil

Mesenchymal stromal cells (MSCs) are inherently immunomodulatory through production of inhibiting soluble factors and expression of immunosuppressive cell surface markers. We tested whether activated MSCs qualify for the induction of antigen-specific immune regulation. Bone marrow derived human MSCs were activated by interferon-γ and analyzed for antigen uptake and processing and immune regulatory features including phenotype, immunosuppressive capacity and metabolic activity. To assess whether activated MSC can modulate adaptive immunity, MSCs were pulsed with islet auto-antigen (GAD65) peptide to stimulate GAD65-specific T-cells. We confirm that inflammatory activation of MSCs increased HLA class II, PD-L1, and intracellular IDO expression, whereas co-stimulatory molecules including CD86 remained absent. MSCs remained locked in their metabolic phenotype, as activation did not alter glycolytic function or mitochondrial respiration. MSCs were able to uptake and process protein. Activated HLA-DR3-expressing MSCs pulsed with GAD65 peptide inhibited proliferation of HLA-DR3-restricted GAD65-specific T-cells, while this HLA class II expression did not induce cellular alloreactivity. Conditioning of antigen-specific T-cells by activated and antigen-pulsed MSCs prevented T-cells to proliferate upon subsequent activation by dendritic cells, even after removal of the MSCs. In sum, activation of MSCs with inflammatory stimuli turns these cells into suppressive cells, capable of mediating adaptive regulation of proinflammatory pathogenic T-cells.

Keywords: Immune Regulation, type 1 diabetes, Antigen specific, Immunotherapy, mesenchymal stromal cell (MSC), Antigen presenting cell

Received: 18 Jul 2018; Accepted: 13 Mar 2019.

Edited by:

Anne Fletcher, Monash University, Australia

Reviewed by:

Masahide Tone, Cedars-Sinai Medical Center, United States
Alain Le Moine, Free University of Brussels, Belgium  

Copyright: © 2019 Van Megen, van 't Wout [, Lages Motta, Dekker, Nikolic and Roep. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Bart O. Roep, City of Hope National Medical Center, Duarte, United States, broep@coh.org