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 Gr1high and increased numbers of Gr1low) 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.
Original language | English (US) |
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Pages (from-to) | 170-181 |
Number of pages | 12 |
Journal | Autoimmunity |
Volume | 50 |
Issue number | 3 |
DOIs | |
State | Published - Apr 3 2017 |
Keywords
- BM-MDSCs
- CEBPβ
- IBD
- MDSCs
- experimental colitis
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology