Aberrant function of myeloid-derived suppressor cells (MDSCs) in experimental colitis and in inflammatory bowel disease (IBD) immune responses. (3rd April 2017) - Kontaki, Eleni
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 −/low CD33 + 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.