The CXCR4-CXCL12 axis promotes T cell reconstitution via efficient hematopoietic immigration
The CXCR4-CXCL12 axis promotes T cell reconstitution via efficient hematopoietic immigration
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CXCR4-CXCL12轴通过有效的造血迁移促进T细胞重建
DOI：
10.1016/j.jgg.2022.04.005
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发表时间：
--
影响因子：
5.9
通讯作者：
Li Li
中科院分区：
文献类型：
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作者：
Fangying Zhao;Yafang Lu;Zhifan Li;Jiangyong He;Nianfei Cui;Lingfei Luo;Li Li
T细胞在抵抗病原体和恶性细胞的免疫中起着至关重要的作用。T细胞免疫缺陷是有害的，特别是当T细胞在严重感染、放疗、化疗和年龄相关性胸腺萎缩期间发生扰动时。因此，促进T细胞重建的策略提供了相当大的好处，值得深入研究。在这里，我们构建了一种用甲硝唑治疗TG(coro1a：DenNTR)斑马鱼的T细胞消融模型。治疗后6.5天，T细胞完全恢复正常。新生的T细胞主要来源于肾脏的造血细胞的迁移，肾脏是骨髓的功能同源物。Cxcr4b基因在反应性造血细胞中表达上调。CXCR4通过遗传和化学机制对T淋巴细胞的功能干扰不是很大，但通过破坏造血迁移而延迟T细胞的再生。相比之下，cxcr4b加速了胸腺中造血细胞的补充。相应地，CXCR4的配体Cxcl12b在损伤动物的胸腺上皮细胞中表达增加。与Cxcr4b类似，Cxcl12b的表达减少或增加会导致T细胞恢复受损或加速。因此，我们的研究揭示了CXCR4-CXCL12信号在促进T细胞恢复中的作用，并为T细胞损伤所致免疫缺陷的治疗提供了一个有希望的靶点。
T cells play critical roles in immunity to protect against pathogens and malignant cells. T cell immunodeficiency is detrimental, especially when T cell perturbation occurs during severe infection, irradiation, chemotherapy, and age-related thymic atrophy. Therefore, strategies that enhance T-cell reconstitution provide considerable benefit and warrant intensive investigation. Here, we constructed a T-cell ablation model in Tg(coro1a:DenNTR) zebrafish via metronidazole administration. T cells completely recovered at 6.5 days post-treatment. The nascent T cells were mainly derived from the migration of hematopoietic cells from the kidney, the functional homolog of bone marrow. The cxcr4b gene was upregulated in the responsive hematopoietic cells. Functional interference of CXCR4 via both genetic and chemical mechanisms did not greatly affect T lymphopoiesis, but delayed T-cell regeneration by disrupting hematopoietic migration. In contrast, cxcr4b accelerated the replenishment of hematopoietic cells in the thymus. Correspondingly, Cxcl12b, a ligand of Cxcr4, was increased in the thymic epithelial cells of the injured animals. Decreased or increased expression of Cxcl12b resulted in compromised or accelerated T-cell recovery, similar to those observed with Cxcr4b. Therefore, our study reveals a role of CXCR4-CXCL12 signaling in promoting T-cell recovery and provides a promising target for the treatment of immunodeficiency due to T cell injury.