Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation
Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation
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DOI：
10.4049/jimmunol.0802631
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Burakoff, Steven
中科院分区：
文献类型：
--
作者：
Alzabin, Saba;Bhardwaj, Nina;Burakoff, Steven
造血祖激酶1 （HPK1）是Ste20激酶的造血细胞限制性成员，通过AP-1、NFAT和NF κ B途径作为T细胞功能的负调节因子。使用HPK1缺陷（HPK1(-/-)）小鼠，我们在本研究中报道了HPK1在树突状细胞（dc）中的新作用。具体来说，我们观察到成熟的HPK1（-/-）骨髓来源的dc （bmdc）在体内和体外刺激T细胞增殖方面优于野生型（WT）。HPK1(-/-) BMDCs的几个特征可能解释了这种增强的活性：成熟的HPK1(-/-) BMDCs表达更高水平的共刺激分子CD80、CD86和I-A(b)，并产生更多的促炎细胞因子IL-12、IL-1 β、tnf - α和IL-6。HPK1作为促凋亡分子的作用在LPS激活后被评估，结果表明HPK1(-/-) BMDCs对LPS诱导的凋亡具有显著的抗性。我们的研究结果促使我们研究HPK1(-/-) BMDCs在肿瘤免疫治疗中的作用。通过对小鼠Lewis肺癌模型的研究，我们发现HPK1(-/-) bmdc比其WT对应体更有效地消除已建立的sc Lewis肺癌。我们的数据揭示了HPK1作为DC功能负调节因子的新作用，确定了其作为DC免疫治疗癌症的分子靶点的潜力。免疫学杂志，2009,32(2):6187-6194。
Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 kinases that acts as a negative regulator of T cell functions through the AP-1, NFAT, and NF kappa B pathways. Using HPK1-deficient (HPK1(-/-)) mice, we report ill this study a novel role for HPK1 in dendritic cells (DCs). Specifically, we observed that matured HPK1(-/-) bone marrow-derived DCs (BMDCs) are superior to their wild-type (WT) counterpart in stimulating T cell proliferation in vivo and in vitro. Several characteristics of HPK1(-/-) BMDCs may account for this enhanced activity: Matured HPK1(-/-) BMDCs express higher levels of costimulatory molecules CD80, CD86, and I-A(b) as well as produce more proinflammatory cytokines IL-12, IL-1 beta, TNIF-alpha, and IL-6 than their WT littermates. The role of HPK1 as a proapoptotic molecule was assessed post activation with LPS, and results indicated that HPK1(-/-) BMDCs are significantly resistant to LPS-induced apoptosis. Our results led us to investigate the role of HPK1(-/-) BMDCs in tumor immunotherapy. Using a s.c. murine model of Lewis Lung Carcinoma, we found that HPK1(-/-) BMDCs eliminate established s.c. Lewis Lung Carcinoma more efficiently than their WT counterpart. Our data reveal a novel role for HPK1 as a negative regulator of DC functions, identifying its potential as a molecular target for DC-based immunotherapy against cancers. The Journal of Immunology, 2009, 182: 6187-6194.