Granzyme C supports efficient CTL-mediated killing late in primary alloimmune responses.
Granzyme C supports efficient CTL-mediated killing late in primary alloimmune responses.
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DOI：
10.4049/jimmunol.181.11.7810
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Thiele DL
中科院分区：
文献类型：
--
作者：
Getachew Y;Stout-Delgado H;Miller BC;Thiele DL
颗粒酶A和B通过穿孔素依赖性颗粒胞吐途径在CTL杀伤靶细胞中发挥作用。在CTL中表达的多个额外的颗粒酶的功能不太清楚。本研究利用二肽基肽酶1（DPP 1）缺陷小鼠产生的CTL，研究颗粒酶C对CTL杀伤同种异体靶细胞的作用。通过蛋白水解除去颗粒酶A和B的N-末端二肽前结构域来活化颗粒酶A和B需要DPP 1，而颗粒酶C的显著部分在没有DPP 1的情况下正常加工。与野生型CTL相比，体外早期（5天）MLC和体内初始同种异体致敏后5天腹腔渗出液细胞中产生的DPP 1-/- CTL的细胞毒性显著受损。然而，用新鲜同种异体刺激物再刺激3天后，这些DPP 1-/-效应细胞的细胞毒性与野生型CTL的细胞毒性相当。再刺激后DPP 1-/- CTL介导的杀伤是快速的，穿孔素依赖性的，Fas不依赖性的，与早期线粒体损伤，磷脂酰丝氨酸外化和DNA降解相关，暗示颗粒酶依赖性凋亡途径。再刺激后DPP 1-/- CTL的细胞毒性增加与颗粒酶C的表达增加相一致。此外，再刺激期间小干扰RNA对颗粒酶C表达的抑制显着降低了DPP 1-/-的细胞毒性，但对野生型CTL的细胞毒性没有影响。这些结果表明，在晚期原发性同种异体免疫应答期间，在功能性颗粒酶A或B不存在的情况下，颗粒酶C可以通过颗粒胞吐途径支持CTL介导的杀伤。
It is well established that granzymes A and B play a role in CTL killing of target cells by the perforin-dependent granule exocytosis pathway. The functions of multiple additional granzymes expressed in CTL are less well defined. In the present studies, CTL generated from mice deficient in dipeptidyl peptidase 1 (DPP1) were used to investigate the contribution of granzyme C to CTL killing of allogeneic target cells. DPP1 is required for activation of granzymes A and B by proteolytic removal of their N-terminal dipeptide prodomains while a significant portion of granzyme C is processed normally in the absence of DPP1. Cytotoxicity of DPP1-/- CTL generated in early (5-day) MLC in vitro and in peritoneal exudate cells 5 days after initial allogeneic sensitization in vivo was significantly impaired compared with wild-type CTL. Following 3 days of restimulation with fresh allogeneic stimulators however, cytotoxicity of these DPP1-/- effector cells was comparable to that of wild-type CTL. Killing mediated by DPP1-/- CTL following restimulation was rapid, perforin dependent, Fas independent and associated with early mitochondrial injury, phosphatidyl serine externalization, and DNA degradation, implicating a granzyme-dependent apoptotic pathway. The increased cytotoxicity of DPP1-/- CTL following restimulation coincided with increased expression of granzyme C. Moreover, small interfering RNA inhibition of granzyme C expression during restimulation significantly decreased cytotoxicity of DPP1-/- but not wild-type CTL. These results indicate that during late primary alloimmune responses, granzyme C can support CTL-mediated killing by the granule exocytosis pathway in the absence of functional granzymes A or B.
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影响因子：
12.3
作者：
Law RH;Zhang Q;McGowan S;Buckle AM;Silverman GA;Wong W;Rosado CJ;Langendorf CG;Pike RN;Bird PI;Whisstock JC
通讯作者：
Whisstock JC
影响因子：
4.4
作者：
Gunturi, A;Berg, RE;Forman, J
通讯作者：
Forman, J
影响因子：
4.4
作者：
Kelso, A;Costelloe, EO;Fitzpatrick, DR
通讯作者：
Fitzpatrick, DR
影响因子：
32.4
作者：
Beresford, PJ;Xia, ZN;Lieberman, J
通讯作者：
Lieberman, J
影响因子：
20.3
作者：
Johnson, H;Scorrano, L;Ley, TJ
通讯作者：
Ley, TJ