Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes
Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes
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DOI：
10.1182/blood-2007-01-071167
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发表时间：
2007-12-01
期刊：
影响因子：
20.3
通讯作者：
Arnold, Ruediger
中科院分区：
文献类型：
--
作者：
Brenner, Dirk;Golks, Alexander;Arnold, Ruediger
外周淋巴细胞的生死受到严格控制，以维持T细胞和B细胞的生理水平。激活诱导的细胞死亡 (AICD) 是通过重新刺激免疫受体来消除多余淋巴细胞的一种机制，它部分取决于 CD95/CD95L 系统。最近，我们发现造血祖细胞激酶 1 (HPK1) 决定 T 细胞的命运。虽然全长 HPK1 对于 T 细胞中 NF-KB 的激活至关重要，但 HPK1 的 C 末端片段 HPK1-C 可抑制 NF-KB 并通过尚未明确的细胞死亡途径对 AICD 敏感。在这里，我们表明，在 IL-2 驱动的原代 T 细胞扩增后，HPK1 通过低于凋亡诱导阈值的 caspase-3 活性转化为 HPK1-C。 HPK1-C 选择性阻断 NF-κ B 依赖性抗凋亡 Bcl-2 家族成员的诱导，但不阻断促凋亡 Bcl-2 家族成员 Bim 的诱导。有趣的是，来自 HPK1-C 转基因小鼠的 T 和 B 淋巴细胞独立于 CD95/CD95L 系统进行 AICD，但涉及 caspase-9。通过小干扰RNA敲低HPK1/HPK1-C或Bim表明，CD95L依赖性和HPK1/HPK1-C依赖性细胞死亡途径在原代T细胞的AICD中相互补充。我们的结果将 HPK1-C 定义为抗凋亡 Bcl-2 蛋白的抑制剂，并为我们理解淋巴细胞的 CD95L 依赖性 AICD 提供了分子基础。
Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.