Haile Lydia A, von Wasielewski Reinhard, Gamrekelashvili Jaba, Krüger Christine, Bachmann Oliver, Westendorf Astrid M, Buer Jan, Liblau Roland, Manns Michael P, Korangy Firouzeh, Greten Tim F
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
Gastroenterology. 2008 Sep;135(3):871-81, 881.e1-5. doi: 10.1053/j.gastro.2008.06.032. Epub 2008 Jun 12.
BACKGROUND & AIMS: CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) have been shown to cause T-cell tolerance in tumor-bearing mice; however, little is known about the role of MDSCs in chronic inflammation. Here, for the first time, we have identified and analyzed their role in inflammatory bowel disease (IBD).
Repetitive adoptive transfer of clone 4/T-cell receptor (CL4-TCR) transgenic CD8(+) T cells into VILLIN-hemagglutinin (HA) transgenic mice was performed on days 1, 12, and 27. Recipient mice were analyzed for immunopathology, HA-specific CD8(+) T-cell responses, and CD11b(+)Gr-1(+) MDSCs (frequency, phenotype, expression analysis, and in vitro as well as in vivo function). In addition, peripheral blood from patients with active Crohn's disease and ulcerative colitis was examined for the presence and function of human MDSCs denoted as CD14(+)HLA-DR(-/low) cells.
Repetitive transfer of HA-specific CD8(+) T cells prevented VILLIN-HA recipient mice from development of severe enterocolitis, which is seen after a single transfer of T cells. Repeated transfer of antigen-specific T cells led to an increase in the frequency of nitric oxide synthase 2 and arginase-expressing CD11b(+)Gr-1(+) MDSCs in spleen and intestine of VILLIN-HA mice with immunosuppressive function. Cotransfer of MDSCs with HA-specific CD8(+) T cells into naive VILLIN-HA mice ameliorated enterocolitis, indicating a direct immune regulatory effect of MDSCs on induction of IBD by antigen-specific T cells. Finally, an increase in the frequency of human MDSCs with suppressor function was observed in peripheral blood from patients with IBD.
These results identify MDSCs as a new immune regulatory pathway in IBD.
已证实CD11b(+)Gr-1(+)髓源性抑制细胞（MDSCs）可在荷瘤小鼠中诱导T细胞耐受；然而，关于MDSCs在慢性炎症中的作用却知之甚少。在此，我们首次鉴定并分析了它们在炎症性肠病（IBD）中的作用。
于第1、12和27天，将克隆4/T细胞受体（CL4-TCR）转基因CD8(+) T细胞重复过继转移至VILLIN-血凝素（HA）转基因小鼠体内。对受体小鼠进行免疫病理学、HA特异性CD8(+) T细胞应答以及CD11b(+)Gr-1(+) MDSCs（频率、表型、表达分析以及体内外功能）分析。此外，检测了活动性克罗恩病和溃疡性结肠炎患者外周血中标记为CD14(+)HLA-DR(-/低)细胞的人MDSCs的存在及功能。
HA特异性CD8(+) T细胞的重复转移可使VILLIN-HA受体小鼠免于发生严重小肠结肠炎，而单次转移T细胞后则会出现这种情况。抗原特异性T细胞的重复转移导致VILLIN-HA小鼠脾脏和肠道中表达一氧化氮合酶2和精氨酸酶的具有免疫抑制功能的CD11b(+)Gr-1(+) MDSCs频率增加。将MDSCs与HA特异性CD8(+) T细胞共同转移至未致敏的VILLIN-HA小鼠体内可改善小肠结肠炎，表明MDSCs对抗原特异性T细胞诱导IBD具有直接免疫调节作用。最后，在IBD患者外周血中观察到具有抑制功能的人MDSCs频率增加。
这些结果确定MDSCs是IBD中一种新的免疫调节途径。
