Characterization of mucosal intranet formed by γδ/αβ T cells and epithelial cells

γδ/αβ T 细胞和上皮细胞形成的粘膜内网的表征

• 批准号: 09307006
• 负责人: KIYONO Hiroshi
• 金额: $ 19.52万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09307006/
• 关键词: Mucosal immune system; Mucosal intranet; Epithelial cell; Mucosal T cells; IgA; Peyer's patch; B-1; B-2 cells; 粘膜細胞間インターネット; 粘膜細胞間イントラネット; 粘膜免疫機構; 粘膜誘導型寛容; 経口免疫寛容; 粘膜系γδT細胞; TCRδ遺伝子欠損マウス; IL-10; 上皮細胞間リンパ球; IgA; コレラ毒素; IL-7; IL-7R; γδT

The common mucosal immune system (CMIS) has been shown to be a key element which bridges between inductive (e.g. PP in the intestinal tract) and effector (e.g. i-LP) tissues for the induction of antigen-specific IgA response. However, our recent investigations provided new evidence that the IgA antibody response can be induced in an CMIS-independent manner via a B-1 lineage of IgA committed B cells. In contrast to the CMIS-dependent B-2 cells (IL-5R^+ and IL-6R^+), B-1 cells are under the regulation of a T cell independent cytokine IL-15/IL-15R signaling cascade in addition to the Th2 type IL-5/IL-5R pathway. These findings suggest that the mucosal immune system is equipped with both CMIS-dependent (B-2) and-independent (B-1) pathways for the induction of an IgA responses.For the induction of chronic inflammation in the large intestine, we showed that immunopathological lymphocytes were a unique subset of thymus derived mucosal ββ T cells of the Th2-type (i.e. IL-4 producer). Removal of these cells by treatment With mAbs specific for TCRβ3 and IL-4 resulted in the inhibition of colitis development. With regard to intestinal allergy, our new OVA-induced model provides the first direct evidence that a Th2-type cell mediated local accumulation of mast cells, eosinophils, and IgE plasma cells in colon is associated with the induction of allergic symptoms. Further, it was shown that systemically originating antigen-specific Th2-type cells preferentially homed to the large intestine for STAT6-mediated IL-4 and IL-13 synthesis. Although chronic inflammation and allergic reaction represent two totally different immunological diseases, an interesting aspect of our findings is that CD4^+ T cells originating from the systemic compartment played a key role in the development of a disease condition in a remote mucosal compartment such as the large intestine.

共同的粘膜免疫系统（CMIS）已被证明是一个关键要素，在电感（例如肠道中的PP）和效应子（例如I-LP）组织之间桥接以诱导抗原特异性IGA响应。但是，我们最近的研究提供了新的证据，表明可以通过IgA承诺的B细胞的B-1谱系以CMIS独立的方式诱导IgA抗体反应。与CMIS依赖性的B-2细胞（IL-5R^+和IL-6R^+）相反，B-1细胞除了TH2型IL-5/IL-5R途径外，B-1细胞受T细胞独立的细胞因子IL-15/IL-15R信号级联的调节。这些发现表明，粘膜免疫系统与CMIS依赖性（B-2）和非依赖性（B-1）途径相当于诱导IgA反应的途径。对于大肠中慢性炎症的诱导，我们表明，免疫病理病理学淋巴细胞是胸腺thymus i.Mcosal-mcossβt th2 th2 type i. th2 type i.生产者）。通过特异性的TCRβ3和IL-4处理来清除这些细胞，从而抑制结肠炎发育。关于肠过敏，我们的新OVA诱导的模型提供了第一个直接证据，表明Th2型细胞介导的结肠中肥大细胞，嗜酸性粒细胞和IgE血浆细胞的局部积累与诱导过敏症状有关。此外，结果表明，用于STAT6介导的IL-4和IL-13合成的大肠上的抗原特异性Th2型细胞优先归纳为大肠。尽管慢性感染和过敏反应代表了两种完全不同的免疫疾病，但我们发现的一个有趣的方面是，源自全身室的CD4^+ T细胞在远程粘膜室中疾病状况的发展中起着关键作用，例如大肠。

项目成果

Kawabata, S., Miller, C.J., Lehner, T., Fujihashi, K., Kubota, M., McGhee, J.R.Hiroi, T., and Kiyono, H.: "Induction of polarized Th2 cytokine expression for p27-specific IgA B cell responses after targeted lymphnode immunnization with simian immunodefici

Kawabata, S.、Miller, C.J.、Lehner, T.、Fujihashi, K.、Kubota, M.、McGhee, J.R.Hiroi, T. 和 Kiyono, H.：“诱导 p27 特异性 IgA 的极化 Th2 细胞因子表达

Kweon,M-N. et.al: "Systemically derived large intestinal CD4^+ Th2 cells play a central role for the development of STAT6-mediated allergic diarrhea."J.Clin.Invest. 106. 199-206 (2000)

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Wikox,C.M.,Harris,P.R.,Redman,T.K.,Kawabata,S.,Hiroi,T.,Kiyono,H.,and Smith,P.D.: "High mucosal levels of tumor necrosis factor-α mRNA are associated with cytomegalovirus esphagitis."Gasteroenterology.. 114. 77-82 (1998)

Wikox, C.M.、Harris, P.R.、Redman, T.K.、Kawabata, S.、Hiroi, T.、Kiyono, H. 和 Smith, P.D.：“肿瘤坏死因子-α mRNA 的高粘膜水平与巨细胞病毒性食管炎相关。”胃肠病学.. 114. 77-82 (1998)

Harris,P.R.,Ernst.P.B.,Kawabata,K.,Kiyono,H.,Graham,M.F.and Smith,P.D.: "Recombinant Helicobacter pylori urease activates primary mucosal macrophages."J.Infect.Dis.. 178(5). 1516-1520 (1998)

Harris,P.R.、Ernst.P.B.、Kawabata,K.、Kiyono,H.、Graham,M.F. 和 Smith,P.D.：“重组幽门螺杆菌脲酶激活原代粘膜巨噬细胞。”J.Infect.Dis. 178(5)。