Why T cells of thymic versus extrathymic origin are functionally different
Why T cells of thymic versus extrathymic origin are functionally different
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DOI：
10.4049/jimmunol.180.4.2299
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Perreault, Claude
中科院分区：
文献类型：
--
作者：
Blais, Marie-Eve;Brochu, Sylvie;Perreault, Claude
胸腺萎缩严重损害免疫反应。因此，胸腺外产生T细胞的策略正受到强烈关注。我们已经证明胸腺外产生的T细胞相对于胸腺衍生的T细胞是功能缺陷的。胸腺外T细胞的主要局限性是它们对凋亡的过度敏感性;因此，它们在面对病原体时不能适当地扩增。使用制瘤素M转基因小鼠，我们发现，在没有淋巴细胞减少症，胸腺外起源的T细胞组成性地经历过度的稳态增殖，导致IL-2和IFN-γ的过度产生。IFN-γ上调胸腺外CD 8 T细胞上的Fas和FasL，从而通过Fas介导的凋亡导致其死亡。此外，IFN-γ和可能的IL-2通过下调IL-7 R α和Bcl-2来减少胸腺外CD 4 T细胞的存活，并且它们支持FoxP 3（+）T调节细胞的显著积累。此外，我们表明，野生型胸腺衍生的T细胞在淋巴细胞减少的主机进行稳态增殖共享胸腺外T细胞的关键特征。我们的工作解释了过度的淋巴细胞减少独立的稳态增殖如何使胸腺外T细胞功能缺陷。基于以前的工作和数据，我们提出，胸腺外T细胞进行组成性稳态增殖，因为它们是积极选择淋巴结造血细胞，而不是胸腺上皮细胞。
Age-related thymic involution severely impairs immune responsiveness. Strategies to generate T cells extrathymically are therefore being explored with intense interest. We have demonstrated that T cells produced extrathymically were functionally deficient relative to thymus-derived T cells. The main limitation of extrathymic T cells is their undue susceptibility to apoptosis; they thus do not expand properly when confronted with pathogens. Using oncostatin M-transgenic mice, we found that in the absence of lymphopenia, T cells of extrathymic origin constitutively undergo excessive homeostatic proliferation that leads to overproduction of IL-2 and IFN-gamma. IFN-gamma up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN-gamma and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7R alpha and Bcl-2, and they support a dramatic accumulation of FoxP3(+) T regulatory cells. Additionally, we show that wild-type thymus-derived T cells undergoing homeostatic proliferation in a lymphopenic host shared key features of extrathymic T cells. Our work explains how excessive lymphopenia-independent homeostatic proliferation renders extrathymic T cells functionally defective. Based on previous work and data presented herein, we propose that extrathymic T cells undergo constitutive homeostatic proliferation because they are positively selected by lymph node hemopoietic cells rather than by thymic epithelial cells.