Davidson N J, Leach M W, Fort M M, Thompson-Snipes L, Kühn R, Müller W, Berg D J, Rennick D M
DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304, USA.
J Exp Med. 1996 Jul 1;184(1):241-51. doi: 10.1084/jem.184.1.241.
Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.
白细胞介素10产生缺陷（IL-10-/-）的小鼠会患上一种以结肠为主的慢性炎症性肠病（IBD），其组织病理学特征与人类IBD相似。我们的目的是确定哪种细胞类型可介导IL-10-/-小鼠的结肠炎。我们检测到免疫球蛋白阳性细胞流入结肠，且在IL-10-/-小鼠血清中存在结肠反应性抗体。为评估B细胞的致病作用，我们培育出IL-10-/-小鼠的B细胞缺陷（B-/-）品系。B-/-IL-10-/-小鼠患上了与IL-10-/-小鼠类似的严重结肠炎，这表明在该模型中B细胞并非IBD的主要介导因素。进行了一系列细胞移植实验以评估T细胞的致病作用。当将富含IL-10-/-T细胞的固有层淋巴细胞（LPL）或上皮内淋巴细胞（IEL）移植到免疫缺陷的重组激活基因（RAG）-2-/-受体小鼠体内时，会根据移植的细胞数量发展出轻度至重度的结肠炎。从患有结肠炎的移植RAG-2-/-小鼠结肠中回收的淋巴细胞主要是αβTCR+CD4+，其中包括很大比例的CD4+CD8α+细胞。这些细胞也是CD45RB-/低表达和CD44+，表明是活化/记忆细胞群体。然后从IL-10-/-小鼠的固有层中分离出CD4+CD8α-、CD4+CD8α+和CD4-CD8α+T细胞的单个群体，并移植到RAG-2-/-受体小鼠体内。只有表达IL-10-/-CD4的LPL，包括CD4+CD8α-和CD4+CD8α+群体，能在受体小鼠中诱发结肠炎。从患有结肠炎的RAG-2-/-受体小鼠发炎结肠中回收的CD4+CD8α-和CD4+CD8α+LPL产生干扰素-γ，但几乎不产生或不产生IL-4，这表明是α辅助性T细胞1（TH1）介导的反应。因此，我们得出结论，IL-10-/-小鼠的结肠炎主要由单独表达CD4或与CD8α分子联合表达的TH1型αβTCR+T细胞介导。
