Serine protease inhibitor 6 plays a critical role in protecting murine granzyme B-producing regulatory T cells.
Serine protease inhibitor 6 plays a critical role in protecting murine granzyme B-producing regulatory T cells.
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DOI：
10.4049/jimmunol.1300851
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Abdi R
中科院分区：
文献类型：
--
作者：
Azzi J;Skartsis N;Mounayar M;Magee CN;Batal I;Ting C;Moore R;Riella LV;Ohori S;Abdoli R;Smith B;Fiorina P;Heathcote D;Bakhos T;Ashton-Rickardt PG;Abdi R
调节性t细胞（Regulatory t cells, Tregs）在维持免疫耐受中起着关键作用，在多种免疫介导疾病的细胞治疗中具有很大的前景。然而，调控Treg维持和体内平衡的细胞机制尚未被充分探索。虽然treg表达GrB （Granzyme-B）通过直接杀伤抑制效应t细胞，但它们保护自己免受GrB介导的自我伤害的机制尚不清楚。我们首次发现iTregs和nTregs在激活GrB及其内源性抑制剂丝氨酸蛋白酶抑制剂-6 （Spi6）后，细胞内表达均增加。亚细胞分离和细胞质中GrB活性的测量表明，活化的Spi6−/−Tregs具有显著更高的细胞质GrB活性。我们在体外观察到grb介导的Spi6−/−nTregs细胞凋亡增加，异体反应性t细胞抑制受损。在体外，添加GrB抑制剂（Z-AAD-CMK）可使Spi6−/−Tregs免于凋亡。此外，我们的体内生物发光成像显示，过继转移实验表明，由于Spi6−/−nTregs的存活受损，其抑制移植物抗宿主病（GVHD）的效果不如WT nTregs。最后，与WT受体相比，spi6缺陷受体以更快的速度排斥MHC ii类不匹配的心脏同种异体移植物，并且在treg中显示出更高的凋亡率。我们的数据首次证明了Spi6在Treg稳态中的新作用，通过保护活化的Treg免受grb介导的损伤。这些数据可能对基于treg的免疫介导性疾病治疗具有重要的临床意义。
Regulatory T-cells (Tregs) play a pivotal role in the maintenance of immune tolerance and hold great promise as cell therapy for a variety of immune-mediated diseases. However, the cellular mechanisms that regulate Treg maintenance and homeostasis have yet to be fully explored. While Tregs express Granzyme-B (GrB) to suppress effector T-cells via direct-killing, the mechanisms by which they protect themselves from GrB-mediated self-inflicted damage are unknown. We show, for the first time, that both iTregs and nTregs increase their intracellular expression of GrB and its endogenous inhibitor, Serine Protease Inhibitor-6 (Spi6) upon activation. Sub-cellular fractionation and measurement of GrB activity in the cytoplasm of Tregs show that activated Spi6−/− Tregs had significantly higher cytoplasmic GrB activity. We observed an increase in GrB-mediated apoptosis in Spi6−/− nTregs and impaired suppression of alloreactive T-cells in vitro. Spi6−/− Tregs were rescued from apoptosis by the addition of a GrB inhibitor (Z-AAD-CMK) in vitro. Furthermore, adoptive transfer experiments showed that Spi6−/− nTregs were less effective than WT nTregs in suppressing Graft-versus-host-disease (GVHD) due to their impaired survival, as shown in our in vivo bioluminescence imaging. Finally, Spi6-deficient recipients rejected MHC class II-mismatch heart allografts at a much faster rate and showed a higher rate of apoptosis among Tregs, as compared to WT recipients. Our data demonstrate, for the first time, a novel role for Spi6 in Treg homeostasis by protecting activated Tregs from GrB-mediated injury. These data could have significant clinical implications for Treg-based therapy in immune-mediated diseases.
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DOI：
10.4049/jimmunol.1102667
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lovo E;Zhang M;Wang L;Ashton-Rickardt PG
通讯作者：
Ashton-Rickardt PG
影响因子：
4.1
作者：
Annand, RR;Dahlen, JR;Giegel, DA
通讯作者：
Giegel, DA
影响因子：
32.4
作者：
Cao, Xuefang;Cai, Sheng F.;Ley, Timothy J.
通讯作者：
Ley, Timothy J.
影响因子：
4.4
作者：
Schenk, S;Kish, DD;Fairchild, RL
通讯作者：
Fairchild, RL
影响因子：
8.9
作者：
Stewart, S;Winters, GL;Billingham, ME
通讯作者：
Billingham, ME