MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota
MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota
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DOI：
10.1016/j.immuni.2019.08.011
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发表时间：
2019-11-19
期刊：
影响因子：
32.4
通讯作者：
Hill, Geoffrey R.
中科院分区：
文献类型：
--
作者：
Koyama, Motoko;Mukhopadhyay, Pamela;Hill, Geoffrey R.
胃肠道移植物抗宿主病(GVHD)是异基因骨髓移植(BMT)后致死率的主要决定因素。在这里，我们研究了启动GVHD的机制，包括相关的抗原提呈细胞。MHCⅡ类分子稳定表达于回肠内的肠上皮细胞，而在无菌小鼠的肠上皮细胞中不表达。IEC特异性的MHC II类缺失可防止胃肠道致死性移植物抗宿主病的发生。缺乏TLR接头MyD88和TRIF且需要固有层淋巴细胞分泌干扰素的小鼠，IEC上MHC-II类分子表达缺失。干扰素伽玛反应的特点是由髓系细胞分泌IL-12驱动的。抗生素介导的微生物区系枯竭抑制了回肠巨噬细胞产生IL-12/23p40。IL-12/23p40中和可阻止IECS上MHC II类分子的上调和胃肠道致死性移植物抗宿主病的发生。因此，IECS在回肠表达MHCClass II启动了致死性GVHD，阻断IL-12/23p40可能是一种易于翻译的治疗策略。
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion ofMHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent frommice deficient in the TLR adaptors MyD88 and TRIF and required IFN gamma secretion by lamina propria lymphocytes. IFN gamma responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHCclass II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.