Aberrant function of myeloid-derived suppressor cells (MDSCs) in experimental colitis and in inflammatory bowel disease (IBD) immune responses

Abstract

Background and aims: Myeloid-derived suppressor cells (MDSCs) encompass a novel population of suppressor cells and a potential candidate for cell-based therapies in inflammatory diseases. Herein, we investigated their immunomodulatory properties in experimental inflammatory colitis and T cell-mediated immune responses in inflammatory bowel disease (IBD) patients. Methods: MDSCs (defined as CD14⁻HLA⁻DR^−/lowCD33⁺CD15⁺) numbers were determined in peripheral blood (PB) from IBD patients. PB MDSC function was assessed in vitro. Experimental colitis was induced upon 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment and MDSCs were characterized by flow cytometry. The in vivo suppressive potential of bone marrow (BM)-derived MDSCs (BM-MDSCs) was tested by using both depleting and adoptive transfer strategies. Results: MDSCs were enriched in the periphery of IBD patients during active disease. TNBS colitis induced amplification of MDSCs, particularly of the granulocytic (Ly6G⁺) subset during the effector phase of disease. Of interest, BM-MDSCs potently suppressed CD4⁺T cell responses under steady state but failed to control colitis-associated immune responses in vivo. Mechanistically, under the colonic inflammatory milieu MDSCs switched phenotype (decreased proportion of Gr1^high and increased numbers of Gr1^low) and downregulated CCAAT/enhancer-binding protein beta (CEBPβ) expression, a critical transcription factor for the suppressive function of MDSCs. In accordance with the murine data, human CD33 ⁺ CD15⁺MDSCs from peripheral blood of IBD patients not only failed to suppress autologous T cell responses but instead enhanced T cell proliferation in vitro. Conclusions: Our findings demonstrate an aberrant function of MDSCs in experimental inflammatory colitis and in IBD-associated immune responses in vitro. Delineation of the mechanisms that underlie the loss of MDSCs function in IBD may provide novel therapeutic targets.

Keywords:

• MDSCs
• BM-MDSCs
• IBD
• experimental colitis
• CEBPβ

Acknowledgements

The authors thank M. Ioannou and C. Choulaki, for assisting with experiments; Z. Vlata, N. Gounalaki, and T. Makatounakis for technical assistance with cell sorting, E. Choustoulaki for patient care, M. Tzardi for histology preparations, and I. Drygiannakis for review of the manuscript.

Disclosures

The authors report no conflicts of interest. This work was supported by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) – Research Funding Program: Heraclitus II 3396. Investing in knowledge society through the European Social Fund, the Greek General Secretariat of Research and Technology [Aristeia II 3468 to P.V.] and European Union project Innovative Medicine Initiative 6 [“BeTheCure”, Contract no. 115142-2, to P.V. and D.B.].