Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate
Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate
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DOI：
10.1073/pnas.1011556107
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发表时间：
2010-09-14
影响因子：
11.1
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
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作者：
Beinke, Soeren;Phee, Hyewon;Weiss, Arthur
T细胞与抗原呈递细胞的相互作用对于CD 8 T细胞效应或记忆命运决定是重要的。整合素白细胞功能相关抗原-1（LFA-1）介导T细胞粘附，但对LFA-1诱导的信号通路对T细胞应答的贡献知之甚少。在这里，我们证明了富含脯氨酸的酪氨酸激酶-2（PYK 2）缺乏通过协同LFA-1和T细胞受体刺激损害CD 8 T细胞活化。此外，PYK 2对于LFA-1介导的CD 8 T细胞粘附和LFA-1共刺激CD 8 T细胞迁移是必需的。在体内淋巴细胞性脉络丛脑膜炎病毒感染期间，PYK 2缺陷导致短期效应CD 8 T细胞的特异性损失，但不影响记忆前体CD 8 T细胞的发育。类似地，LFA-1的缺乏主要损害短寿命效应细胞的产生。因此，PYK 2促进LFA-1依赖性CD 8 T细胞应答并促进CD 8 T细胞短期效应物命运，表明PYK 2可能是抑制恶化的CD 8 T细胞应答的令人感兴趣的治疗靶标。
T-cell interactions with antigen-presenting cells are important for CD8 T-cell effector or memory fate determination. The integrin leukocyte function-associated antigen-1 (LFA-1) mediates T-cell adhesion but the contribution of LFA-1-induced signaling pathways to T-cell responses is poorly understood. Here we demonstrate that proline-rich tyrosine kinase-2 (PYK2) deficiency impairs CD8 T-cell activation by synergistic LFA-1 and T-cell receptor stimulation. Furthermore, PYK2 is essential for LFA-1-mediated CD8 T-cell adhesion and LFA-1 costimulation of CD8 T-cell migration. During lymphocytic choriomeningitis virus infection in vivo, PYK2 deficiency results in a specific loss of short-lived effector CD8 T cells but does not affect memory-precursor CD8 T-cell development. Similarly, lack of LFA-1 primarily impairs the generation of short-lived effector cells. Thus, PYK2 facilitates LFA-1-dependent CD8 T-cell responses and promotes CD8 T-cell short-lived effector fate, suggesting that PYK2 may be an interesting therapeutic target to suppress exacerbated CD8 T-cell responses.