Jak3 negatively regulates dendritic-cell cytokine production and survival.
Jak3 negatively regulates dendritic-cell cytokine production and survival.
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DOI：
10.1182/blood-2005-02-0769
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发表时间：
2005-11
期刊：
影响因子：
20.3
通讯作者：
K. Yamaoka;B. Min;Yong-jie Zhou;W. Paul;J. O’Shea
中科院分区：
文献类型：
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作者：
K. Yamaoka;B. Min;Yong-jie Zhou;W. Paul;J. O’Shea
细胞因子对于调节不同细胞的发育和功能至关重要。 Janus 激酶 3 (Jak3) 是一种在造血细胞中表达的酪氨酸激酶，与常见的 γ 链 (gammac) 相关，是白介素 2 (IL-2)、IL-4、IL-7、IL-9、IL-15 和 IL-21 等细胞因子家族信号传导所必需的； Jak3 或 gammac 缺陷会导致严重的联合免疫缺陷 (SCID)。虽然 Jak3 对于淋巴细胞发育至关重要，但 Jak3 在调节树突状细胞 (DC) 中的潜在作用尚不清楚。在此，我们表明，尽管 Jak3-/- 小鼠中不存在 CD8+CD11c+ 脾 DC，但骨髓来源的 DC 在体外由 Jak3-/- 前体细胞正常发育。事实上，Jak3-/- DC 的存活率得到了增强，并且它们表达了较低水平的促凋亡蛋白。 Jak3-/- DC表现出正常的抗原摄取和共刺激分子的上调。然而，Jak3-/- DCs 响应 Toll 样受体配体产生更多的 IL-12 和 IL-10，这与体内 T 辅助细胞 1 (Th1) 分化增强相关。总之，Jak3 对于 DC 开发并不是必需的，但出乎意料的是，它似乎是一个重要的负调节因子。这些结果可能对接受造血干细胞移植的 SCID 患者和可能接受 Jak3 抑制剂治疗的患者具有临床意义。
Cytokines are critical in regulating the development and function of diverse cells. Janus kinase 3 (Jak3) is a tyrosine kinase expressed in hematopoietic cells that associates with the common gamma chain (gammac) and is required for signaling for a family of cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21; deficiency of either Jak3 or gammac results in severe combined immunodeficiency (SCID). While Jak3 is essential for lymphoid-cell development, the potential roles for Jak3 in regulating dendritic cells (DCs) were unclear. Herein, we show that although CD8+CD11c+ splenic DCs are absent in Jak3-/- mice, bone marrow-derived DCs developed normally in vitro from Jak3-/- precursor cells. In fact, the survival of Jak3-/- DCs was enhanced, and they expressed lower levels of proapoptotic proteins. Jak3-/- DCs exhibited normal antigen uptake and up-regulation of costimulatory molecules. However, Jak3-/- DCs produced more IL-12 and IL-10 in response to Toll-like receptor ligands, which correlated with enhanced T helper 1 (Th1) differentiation in vivo. In summary, Jak3 is not essential for DC development but unexpectedly appears to be an important negative regulator. These results may be relevant clinically for patients with SCID who have undergone hematopoietic stem cell transplantation and for patients who might be treated with a Jak3 inhibitor.