Lee Hyun Ju, Ko Jung Hwa, Jeong Hyun Jeong, Ko Ah Young, Kim Mee Kum, Wee Won Ryang, Yoon Sun-Ok, Oh Joo Youn
Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea; and.
Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
J Immunol. 2015 Apr 15;194(8):3634-45. doi: 10.4049/jimmunol.1402139. Epub 2015 Mar 13.
Exogenously administered mesenchymal stem/stromal cells (MSCs) suppress autoimmunity despite transient engraftment. However, the mechanism is unclear. In this study, we report a novel mechanism by which MSCs modulate the immune system by recruiting myeloid-derived suppressor cells in a mouse model of experimental autoimmune uveitis (EAU). Intravenous infusion of MSCs blocked EAU development and reduced Th1 and Th17 responses. Time course analysis revealed an increase of MHC class II(lo)Ly6G(-)Ly6C(hi)CD11b(+) cells in draining lymph nodes by MSCs. These Ly6C(hi)CD11b(+) cells suppressed CD4(+) cell proliferation and Th1/Th17 differentiation and induced CD4(+) cell apoptosis. Adoptive transfer of Ly6C(hi)CD11b(+) cells ameliorated EAU, whereas depletion of Ly6C(hi)CD11b(+) cells abrogated the effects of MSCs. 1.8% of MSCs were present in draining lymph nodes 1 d after infusion, and MSCs with CCL2 knockdown did not increase MHC class II(lo)Ly6G(-)Ly6C(hi)CD11b(+) cells and failed to attenuate EAU. Therefore, our findings demonstrate that MSCs suppress autoimmunity by recruiting myeloid-derived suppressor cells into sites of inflammation in a CCL2-dependent manner.
外源性给予的间充质干/基质细胞（MSC）尽管短暂植入但仍能抑制自身免疫。然而，其机制尚不清楚。在本研究中，我们报告了一种新机制，即MSC在实验性自身免疫性葡萄膜炎（EAU）小鼠模型中通过募集髓源性抑制细胞来调节免疫系统。静脉输注MSC可阻断EAU的发展并减少Th1和Th17反应。时间进程分析显示，MSC使引流淋巴结中MHC II类（低）Ly6G（-）Ly6C（高）CD11b（+）细胞增加。这些Ly6C（高）CD11b（+）细胞抑制CD4（+）细胞增殖和Th1/Th17分化，并诱导CD4（+）细胞凋亡。过继转移Ly6C（高）CD11b（+）细胞可改善EAU，而去除Ly6C（高）CD11b（+）细胞则消除了MSC的作用。输注后1天，1.8%的MSC存在于引流淋巴结中，敲低CCL2的MSC不会增加MHC II类（低）Ly6G（-）Ly6C（高）CD11b（+）细胞，也无法减轻EAU。因此，我们的研究结果表明，MSC通过以CCL2依赖的方式将髓源性抑制细胞募集到炎症部位来抑制自身免疫。
