Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4+Foxp3+regulatory T cells
Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4+Foxp3+regulatory T cells
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DOI：
10.1111/imm.12241
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发表时间：
2014-06-01
期刊：
影响因子：
6.4
通讯作者：
Chen, Xin
中科院分区：
文献类型：
--
作者：
Hu, Ya;Xiao, Haitao;Chen, Xin
原颗粒蛋白（PGRN）是一种具有免疫抑制特性的多效生长因子。最近，有报道称PGRN是肿瘤坏死因子（TNF）受体的拮抗剂，优先作用于TNFR2。然而，我们和其他研究人员发现，TNF-TNFR2相互作用对于功能性CD4+Foxp3+调节性T （Treg）细胞的激活和扩增至关重要。因此，我们研究了PGRN对TNF诱导的天然小鼠抑制性Treg细胞增殖的影响。与我们之前的报道一致，TNF克服了高度纯化的Treg细胞对t细胞受体刺激的低反应性。此外，在白细胞介素-2存在的情况下，TNF优先刺激未分离CD4细胞中含有的Treg细胞的增殖。TNF对抑制性Treg细胞的这些作用被外源性PGRN显著增强。PGRN的这种作用需要TNF和TNFR2的相互作用，因为PGRN本身并不刺激Treg细胞增殖。PGRN对Treg细胞的作用被抗TNFR2抗体消除，缺乏TNFR2的Treg细胞也对PGRN没有反应。此外，PGRN还增强了效应T细胞对TNF的增殖反应，但程度低于Treg细胞，可能是由于这两种CD4细胞亚群上TNFR2表达水平不同所致。因此，我们的数据清楚地表明，PGRN促进而不是抑制TNF-TNFR2相互作用对Treg细胞的功能后果。
Progranulin (PGRN) is a pleiotropic growth factor with immunosuppressive properties. Recently, it was reported that PGRN was an antagonist of tumour necrosis factor (TNF) receptors, preferentially for TNFR2. However, we and others showed that TNF-TNFR2 interaction was critical for the activation and expansion of functional CD4+Foxp3+ regulatory T (Treg) cells. We therefore examined the effect of PGRN on the proliferation of naturally occurring murine suppressive Treg cells induced by TNF. Consistent with our previous reports, TNF overcame the hyporesponsiveness of highly purified Treg cells to T-cell receptor stimulation. Furthermore, in the presence of interleukin-2, TNF preferentially stimulated proliferation of Treg cells contained in unfractionated CD4 cells. These effects of TNF on suppressive Treg cells were markedly increased by exogenous PGRN. TNF and TNFR2 interactions are required for this effect of PGRN, because the PGRN by itself did not stimulate Treg cell proliferation. The effect of PGRN on Treg cells was abrogated by antibody against TNFR2, and Treg cells deficient in TNFR2 also failed to respond to PGRN. Furthermore, PGRN also enhanced the proliferative responses of effector T cells to TNF, but to a lesser extent than that of Treg cells, presumably caused by the different levels of TNFR2 expression on these two subsets of CD4 cells. Hence, our data clearly show that PGRN promotes, rather than inhibits, the functional consequence of TNF-TNFR2 interaction on Treg cells.