Continuous generation of colitogenic CD4+ T cells in persistent colitis
Continuous generation of colitogenic CD4+ T cells in persistent colitis
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DOI：
10.1002/eji.200737745
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发表时间：
2008-05-01
影响因子：
5.4
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
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作者：
Tomita, Takayuki;Kanai, Takanori;Watanabe, Mamoru
炎症性肠病由于结肠炎CD4（+）细胞的扩张而呈慢性病程。然而，目前尚不清楚持续性疾病是由结肠炎记忆CD4（+）细胞持续再激活产生效应CD4（+）细胞还是由初始细胞持续产生效应CD4（+）细胞驱动的。为了澄清这一问题，我们在不同的时间点将Ly5.2（+）和Ly5.1(+) CD4(+)CD45RB高水平细胞连续过继转移到ag -2（-/-）小鼠体内。我们在这里表明，即使存在预先存在的效应记忆CD4（+）细胞，继发性转移的CD4(+)CD45RB高水平细胞也可以转化为CD4(+)CD44（高）CD62L(-)IL-7R α（高）效应记忆T细胞。虽然结肠炎小鼠的CD4（+）细胞总数与初次移植的细胞数量无关，但初次和二次移植的细胞比例取决于移植细胞数量的比例，而与移植的顺序无关。值得注意的是，我们发现首次转移的CD4（+）细胞产生的ifn - γ和IL-17的量明显低于继发转移的CD4（+）细胞。综上所述，结肠炎持续产生的CD4（+）细胞补偿耗竭的CD4（+）细胞可能是结肠炎持续存在的机制之一。
inflammatory bowel diseases take chronic courses due to the expansion of colitogenic CD4(+) cells. However, it is unclear whether the persistent disease is driven by continuous reactivation of colitogenic memory CD4(+) cells to generate effector CD4(+) cells or by continuous generation of effector CD4(+) cells from naive cells. To clarify this issue, we performed a series of sequential adoptive transfers of Ly5.2(+) and Ly5.1(+) CD4(+)CD45RB high cells into RAG-2(-/-) mice at different time points. We show here that the secondarily transferred CD4(+)CD45RB high cells can be converted to CD4(+)CD44(high) CD62L(-)IL-7R alpha(high) effector-memory T cells even in the presence of pre-existing effector-memory CD4(+) cells. Although the total cell numbers of CD4(+) cells in established colitic mice were consistently equivalent irrespective of the number of primarily transferred cells, the ratio of primarily and secondarily transferred cells was dependent on the ratio of the transferred cell numbers, but not on the order of the transfer. Of note, we found that primarily transferred CD4(+) cells produced significantly lower amounts of IFN-gamma and IL-17 than CD4(+) cells arising from secondary transfer. In conclusion, the continuous generation of colitogenic CD4(+) cells that compensate for exhausted CD4(+) cells may be one of the mechanisms involved in the persistence of colitis.