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

作者：Kontaki Eleni; Boumpas Dimitrios T; Tzardi Maria; Mouzas Ioannis A; Papadakis Konstantinos A; Verginis Panayotis^*

来源：Autoimmunity, 2017, 50(3): 170-181.

DOI：10.1080/08916934.2017.1283405

• MDSCs
• BM-MDSCs
• IBD
• experimental colitis
• CEB beta

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/enhancerbinding protein beta (CEBP beta) 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.

• 出版日期2017