Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells
Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells
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DOI：
10.4049/jimmunol.1203111
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发表时间：
2013-06-01
影响因子：
4.4
通讯作者：
Ishii, Naoto
中科院分区：
文献类型：
--
作者：
Kawabe, Takeshi;Sun, Shu-lan;Ishii, Naoto
脾和皮肤淋巴结内幼稚T细胞的动态平衡增殖提供了记忆表型T细胞。“全身性”增殖反应明显分为快速或缓慢的细胞分裂速度。快速增殖是产生效应记忆T细胞的关键。由于肠道组织固有层中含有丰富的效应记忆T细胞，肠道特异性T细胞的稳态增殖可能对肠道效应记忆T细胞的产生具有重要意义。然而，这种器官特异性的幼稚T细胞的动态平衡增殖还没有被解决。在这项研究中，我们通过将CFSE标记的初始CD4(+)T细胞转移到亚致死剂量照射的小鼠体内，并分别评估供体细胞在肠道、肠系膜淋巴结(MLN)和其他淋巴器官中的分裂和分化，来检测肠道特异的动态平衡增殖。我们发现肠和MLN中的快速增殖细胞群具有肠嗜性的α(4)β(+)(7)Th17表型，它们的产生依赖于共生细菌的存在和OX40的共刺激。肠系膜淋巴清扫显著减少宿主肠道中的Th17细胞数量。此外，FTY720诱导MLN中α(4)β+7IL-17A(+)快速分裂细胞的积聚，并消除了肠道中的供体细胞，表明MLN而不是肠道组织是产生肠道Th17细胞的关键。这些结果表明，MLN在诱导肠嗜性Th17细胞和维持小肠内CD4(+)T细胞的稳态中起着中心作用。
Homeostatic proliferation of naive T cells in the spleen and cutaneous lymph nodes supplies memory phenotype T cells. The "systemic" proliferative responses divide distinctly into fast or slow cell division rates. The fast proliferation is critical for generation of effector memory T cells. Because effector memory T cells are abundant in the lamina propria of the intestinal tissue, "gut-specific" homeostatic proliferation of naive T cells may be important for generation of intestinal effector memory T cells. However, such organ-specific homeostatic proliferation of naive T cells has not yet been addressed. In this study, we examined the gut-specific homeostatic proliferation by transferring CFSE-labeled naive CD4(+) T cells into sublethally irradiated mice and separately evaluating donor cell division and differentiation in the intestine, mesenteric lymph nodes (MLNs), and other lymphoid organs. We found that the fast-proliferating cell population in the intestine and MLNs had a gut-tropic alpha(4)beta(+)(7) Th17 phenotype and that their production was dependent on the presence of commensal bacteria and OX40 costimulation. Mesenteric lymphadenectomy significantly reduced the Th17 cell population in the host intestine. Furthermore, FTY720 treatment induced the accumulation of alpha(4)beta+7IL-17A(+) fast-dividing cells in MLNs and eliminated donor cells in the intestine, suggesting that MLNs rather than intestinal tissues are essential for generating intestinal Th17 cells. These results reveal that MLNs play a central role in inducing gut-tropic Th17 cells and in maintaining CD4(+) T cell homeostasis in the small intestine.