澳大利亚QIMR Berghofer医学研究所Geoffrey R. Hill、Motoko Koyama等研究人员合作发现，肠上皮递呈的MHC II类抗原引发移植物抗宿主病（GVHD），并受微生物群体的影响。相关论文于2019年11月19日发表在《免疫》杂志上。

胃肠道GVHD是同种异体骨髓移植（BMT）后致死率的主要决定因素。对此，研究人员调查了启动GVHD的机制，包括相关的抗原呈递细胞。MHC II类在稳定状态下在回肠内的肠上皮细胞（IEC）上表达，但在无菌小鼠的IEC中不存在。

IEC特异性删除II类MHC可以防止在胃肠道中引发致命的GVHD。TLR接头蛋白MyD88和TRIF缺陷的小鼠缺乏IEC上的MHC II类表达，而固有层淋巴细胞却需要IFNγ分泌。IFNγ应答的特征在于髓样细胞的IL-12分泌。抗生素介导的微生物群落耗竭抑制了回肠巨噬细胞产生IL-12/23p40。IL-12/23p40中和可防止IEC上的MHC II类上调和在胃肠道中引发致死性GVHD。

因此，回肠中IEC通过MHC II类表达可引发致死性GVHD，而阻断IL-12/23p40可能是具有临床转化潜力的治疗策略。

附：英文原文

Title: MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota

Author: Motoko Koyama, Pamela Mukhopadhyay, Iona S. Schuster, Andrea S. Henden, Jan Hülsdünker, Antiopi Varelias, Marie Vetizou, Rachel D. Kuns, Renee J. Robb, Ping Zhang, Bruce R. Blazar, Ranjeny Thomas, Jakob Begun, Nicola Waddell, Giorgio Trinchieri, Robert Zeiser, Andrew D. Clouston, Mariapia A. Degli-Esposti, Geoffrey R. Hill

Issue&Volume: 2019/11/19

Abstract: Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principaldeterminant of lethality following allogeneic bone marrow transplantation (BMT). Here,we examined the mechanisms that initiate GVHD, including the relevant antigen-presentingcells. MHC class II was expressed on intestinal epithelial cells (IECs) within theileum at steady state but was absent from the IECs of germ-free mice. IEC-specificdeletion of MHC class II prevented the initiation of lethal GVHD in the GI tract.MHC class II expression on IECs was absent from mice deficient in the TLR adaptorsMyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responsesare characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediateddepletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages.IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiationof lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileuminitiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatabletherapeutic strategy.

DOI: 10.1016/j.immuni.2019.08.011

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30362-0