IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells.
IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells.
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DOI：
10.4049/jimmunol.1400481
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Turnquist HR
中科院分区：
文献类型：
--
作者：
Matta BM;Lott JM;Mathews LR;Liu Q;Rosborough BR;Blazar BR;Turnquist HR
白细胞介素（IL）-33是最近鉴定的IL-1家族成员，其被提出作为报警蛋白或细胞损伤的内源性信号，以及作为多效性细胞因子起作用。IL-33增强Th 1和Th 2免疫的能力支持其在病原体清除和疾病免疫病理学中的作用。然而，IL-33抑制实验性结肠炎和移植排斥反应，通过扩大调节性T细胞（Treg）通过一个不确定的机制。我们试图确定IL-33对造血细胞的影响，其驱动Treg扩增并成为IL-33施用的治疗益处的基础。在此，我们确定了一个反馈回路，其中由IL-33刺激的常规小鼠CD 11 c+树突状细胞（DC）分泌IL-2以选择性地扩增IL-33 R（ST 2+）抑制性CD 4 + Foxp 3 + Treg。有趣的是，这发生在缺乏经典DC成熟的情况下，并且DC衍生的（先天性）IL-2增加DC和相互作用Treg两者上的ST 2表达。ST 2 + Treg代表Foxp 3+细胞的活化亚群，与它们的ST 2 −对应物相比，被证明是ICOShiCD 44 hi。此外，虽然研究表明IL-33暴露的DC促进Th 2应答，但我们揭示了ST 2 + DC是IL-33介导的体外和体内Treg扩增所需的。因此，我们已经揭示了IL-33和先天性IL-2之间的关系，其促进ST 2 + Treg相对于非Treg的选择性扩增。这些发现确定了免疫细胞中由IL-33驱动的一种新的调节途径，该途径可用于治疗益处或用于Treg在体外和体内的稳健扩增。
Interleukin (IL)-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. Herein, we identify a feedback loop where conventional mouse CD11c+ dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2+) suppressive CD4+Foxp3+ Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2+ Treg represent an activated subset of Foxp3+ cells, demonstrated to be ICOShiCD44hi compared to their ST2− counterparts. Furthermore, while studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2+ DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2+ Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
影响因子：
5.4
作者：
Andrade, Marcus V.;Iwaki, Shoko;Ropert, Catherine;Gazzinelli, Ricardo T.;Cunha-Melo, Jose R.;Beaven, Michael A.
通讯作者：
Beaven, Michael A.
影响因子：
4.4
作者：
Granucci, F;Feau, S;Ricciardi-Castagnoli, P
通讯作者：
Ricciardi-Castagnoli, P
影响因子：
4.4
作者：
Kurowska-Stolarska, Mariola;Kewin, Pete;Xu, Damo
通讯作者：
Xu, Damo