Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells.
Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells.
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DOI：
10.1371/journal.pone.0003465
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Hamad, Abdel Rahim A.
中科院分区：
文献类型：
--
作者：
Mohamood, Abdiaziz S.;Bargatze, Dylan;Xiao, Zuoxiang;Jie, Chunfa;Yagita, Hideo;Ruben, Dawn;Watson, Julie;Chakravarti, Shukti;Schneck, Jonathan P.;Hamad, Abdel Rahim A.
Fas途径是T细胞内稳态的主要调节因子，然而，在体内由Fas途径控制的T细胞群还不是很清楚。虽然CD_4和CD_8单阳性T细胞是野生型小鼠外周T细胞亚群中的两个主要亚群，但在携带Fas(LPR小鼠)或Fas配体(GLD小鼠)功能缺失突变的小鼠中，以CD_4−CD_8−双阴性αβT细胞为主，这些T细胞也表达B220，通常被称为B220+DN T细胞。尽管进行了广泛的分析，但B220+DN T细胞淋巴增殖的基础仍然知之甚少。在这项研究中，我们重新研究了为什么由GLD突变引起的T细胞增殖是由B220+DN T细胞主导的问题。我们结合了以下方法来研究这个问题：基因转录图谱、BrdU标记和细胞凋亡检测。我们的结果显示B220+dN T细胞的增殖和死亡速度比稳定状态下的SP T细胞高得多。高增殖率仅限于肠上皮中的B220+dN T细胞，而高凋亡率在肠上皮和外周均可见。但仅在外周，B220+dN T细胞的凋亡依赖于Fas。当Fas途径基因受损时，外周血B220+dN T细胞的凋亡率降低到与SP T细胞相似的基线水平。在这些正常的凋亡条件下，B220+dN T细胞在外周逐渐聚集，最终导致B220+dN T细胞的淋巴增殖。Fas途径在稳定状态下通过靶向和清除外周的DNT细胞，在调节DNT细胞的组织分布中起着关键作用。这一结果为探讨糖尿病肾病T淋巴细胞增殖的发病机制提供了新的思路。
The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4−CD8− double negative αβ T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells. We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation. The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation.
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DOI：
10.1073/pnas.94.8.3914
发表时间：
1997-04-15
影响因子：
11.1
作者：
Kayagaki, N;Yamaguchi, N;Yagita, H
通讯作者：
Yagita, H
影响因子：
24.5
作者：
DAVIES, MDJ;PARROTT, DMV
通讯作者：
PARROTT, DMV
影响因子：
4.4
作者：
GIESE, T;DAVIDSON, WF
通讯作者：
DAVIDSON, WF
影响因子：
56.9
作者：
Hori, S;Nomura, T;Sakaguchi, S
通讯作者：
Sakaguchi, S
影响因子：
64.8
作者：
DHEIN, J;WALCZAK, H;KRAMMER, PH
通讯作者：
KRAMMER, PH