Polysialic acid governs T-cell development by regulating progenitor access to the thymus
Polysialic acid governs T-cell development by regulating progenitor access to the thymus
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DOI：
10.1073/pnas.0905188106
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发表时间：
2009-07-21
影响因子：
11.1
通讯作者：
Bertozzi, Carolyn R.
中科院分区：
文献类型：
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作者：
Drake, Penelope M.;Stock, Christina M.;Bertozzi, Carolyn R.
虽然聚唾液酸转移酶ST 8 Sia IV在初级和次级人类淋巴器官中表达，但其产物聚唾液酸（polySia）在很大程度上被免疫学家忽视。相比之下，神经系统中的polySia表达和功能已得到很好的表征。在这种情况下，polySia调节细胞粘附、迁移、细胞因子应答和接触依赖性分化。具有挑衅性的是，这些相同的过程是免疫发育和功能的重要组成部分。我们先前确定小鼠多能造血祖细胞使用ST 8 Sia IV在其细胞表面上表达polySia。在这里，我们证明，相对于野生型对照，ST 8 Sia IV-/-小鼠的胸腺细胞总数减少了30%，并伴随着最早的胸腺细胞前体的缺陷。T细胞祖细胞起源于骨髓，并通过未知信号以规则的间隔动员到血液中。我们进行了体内重建实验，其中ST 8 Sia IV-/-祖细胞与野生型细胞竞争以重新填充耗尽或缺陷的免疫亚群。缺乏polySi的祖细胞在T细胞发育中表现出特定的缺陷，因为无法进入胸腺。这种表型可能反映了ST 8 Sia IV-/-祖细胞逃离骨髓小生境的能力降低。总的来说，这些结果提供了证据表明polySia参与造血发育。
Although the polysialyltransferase ST8Sia IV is expressed in both primary and secondary human lymphoid organs, its product, polysialic acid (polySia), has been largely overlooked by immunologists. In contrast, polySia expression and function in the nervous system has been well characterized. In this context, polySia modulates cellular adhesion, migration, cytokine response, and contact-dependent differentiation. Provocatively, these same processes are vital components of immune development and function. We previously established that mouse multipotent hematopoietic progenitors use ST8Sia IV to express polySia on their cell surfaces. Here, we demonstrate that, relative to wild-type controls, ST8Sia IV-/- mice have a 30% reduction in total thymocytes and a concomitant deficiency in the earliest thymocyte precursors. T-cell progenitors originate in the bone marrow and are mobilized to the blood at regular intervals by unknown signals. We performed in vivo reconstitution experiments in which ST8Sia IV-/- progenitors competed with wild-type cells to repopulate depleted or deficient immune subsets. Progenitors lacking polySi exhibited a specific defect in T-cell development because of an inability to access the thymus. This phenotype probably reflects a decreased capacity of the ST8Sia IV-/- progenitors to escape from the bone marrow niche. Collectively, these results provide evidence that polySia is involved in hematopoietic development.