T-helper 17 and Interleukin-17-Producing Lymphoid Tissue Inducer-Like Cells Make Different Contributions to Colitis in Mice
T-helper 17 and Interleukin-17-Producing Lymphoid Tissue Inducer-Like Cells Make Different Contributions to Colitis in Mice
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DOI：
10.1053/j.gastro.2012.07.108
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发表时间：
2012-11-01
期刊：
影响因子：
29.4
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Ono, Yuichi;Kanai, Takanori;Hibi, Toshifumi
背景与目的：表达类维生素A相关孤儿受体（ROR）γ t的T辅助（Th）17细胞有助于小鼠结肠炎的发展，但在正常和发炎的肠中发现。我们研究了它们在小鼠肠道中的发育和功能。方法：我们分析了健康和炎症小鼠肠道组织中的肠道Th 17细胞。我们分析了Th 17细胞和淋巴组织诱导物样细胞的荧光素（LT）α的表达。研究结果：LT alpha（-/-）和ROR gamma t（-/-）小鼠小肠中天然存在的Th 17细胞的百分比显著低于野生型小鼠。与野生型小鼠相比，LT α（-/-）和LT α（-/-）X重组激活基因（RAG）-2（-/-）小鼠中产生白细胞介素-17 A的CD 3（-）CD 4（+/-）白细胞介素-7 R α（+）c-kit（+）CCR 6（+）NKp 46（-）淋巴组织诱导物样细胞的数量增加，但ROR γ t（-/-）小鼠中不存在。野生型和LT α（-/-）小鼠的联体共生和骨髓移植实验表明，LT α依赖性肠道相关淋巴组织结构是产生天然Th 17细胞所必需的。然而，当将野生型或LT α（-/-）CD 4（+）CD 45 RB（高）T细胞转移到RAG-2（-/-）或LT α（-/-）X RAG-2（-/-）小鼠时，所有组，无论供体或受体细胞上是否存在LT α，均发生结肠炎并产生Th 1、Th 17和Th 17/Th 1细胞。接受第二轮移植的RAG-2（-/-）小鼠，具有致大肠杆菌性但不是天然存在的Th 17细胞，发生肠道炎症。小鼠结肠中天然存在的Th 17细胞抑制了转移CD 4（+）CD 45 RB（high）T细胞后结肠炎的发展，并增加了来源于CD 4（+）CD 45 RB（high）T细胞的Foxp 3（+）细胞的数量。结论：肠道相关淋巴组织结构需要产生天然存在的Th 17细胞，这些细胞在小鼠的正常肠道中具有调节活性，但在炎症期间不需要产生致结肠炎性Th 17和Th 17/Th 1细胞。
BACKGROUND & AIMS: T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) gamma t contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice. METHODS: We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)alpha by Th17 cells and lymphoid tissue inducer-like cells. RESULTS: LT alpha(-/-) and ROR gamma t(-/-) mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3(-)CD4(+/-) interleukin-7R alpha(+) c-kit(+) CCR6(+) NKp46(-) lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LT alpha(-/-) and LT alpha(-/-) X recombination activating gene (RAG)-2(-/-) mice, compared with wild-type mice, but were absent from ROR gamma t(-/-) mice. Parabiosis of wild-type and LT alpha(-/-) mice and bone marrow transplant experiments revealed that LT alpha-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LT alpha(-/-) CD4(+)CD45RB(high) T cells were transferred to RAG-2(-/-) or LT alpha(-/-) X RAG-2(-/-) mice, all groups, irrespective of the presence or absence of LT alpha on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2(-/-) mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4(+)CD45RB(high) T cells and increased the numbers of Foxp3(+) cells derived from CD4(+)CD45RB(high) T cells. CONCLUSIONS: Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation.