Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells
Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells
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DOI：
10.1182/blood-2007-06-096875
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Thrasher, Adrian J.
中科院分区：
文献类型：
--
作者：
Bouma, Gerben;Burns, Siobhan;Thrasher, Adrian J.
Wiskott-Aldrich综合征（WAS）的特征在于影响多种免疫细胞谱系的细胞骨架动力学缺陷，并导致免疫缺陷和自身免疫。尽管未成熟和成熟的WAS敲除（KO）DC表现出显著的趋化性和迁移异常，但尚未确定树突状细胞（DC）功能障碍对免疫失调的贡献。为了排除WAS蛋白（WASp）缺乏导致的环境混杂因素，我们研究了过继转移到野生型受体小鼠后WAS KO DC的体内迁移和引发活性。归巢引流淋巴结减少，WAS KO DC未能有效定位于T细胞区域。预载抗原的WAS KO DC对CD 4（+）和CD 8（+）T淋巴细胞的致敏作用显著降低。在低剂量的抗原下，WAS KO DC在体外对预致敏的野生型CD 4 + T淋巴细胞的活化也被废除，这表明即使成功实现DC-T细胞共定位，也存在阈值依赖性损伤。我们的数据表明，由于WASP缺乏导致的固有DC功能障碍直接损害了体内T细胞的引发反应，最有可能是由于迁移效率低下，但也可能受到次优DC介导的同源相互作用的影响。
The Wiskott-Aldrich syndrome (WAS) is characterized by defective cytoskeletal dynamics affecting multiple immune cell lineages, and leading to immunodeficiency and autoimmunity. The contribution of dendritic cell (DC) dysfunction to the immune dysregulation has not been defined, although both immature and mature WAS knockout (KO) DCs exhibit significant abnormalities of chemotaxis and migration. To exclude environmental confounders as a result of WAS protein (WASp) deficiency, we studied migration and priming activity of WAS KO DCs in vivo after adoptive transfer into wild-type recipient mice. Homing to draining lymph nodes was reduced and WAS KO DCs failed to localize efficiently in T-cell areas. Priming of both CD4(+) and CD8(+) T lymphocytes by WAS KO DCs preloaded with antigen was significantly decreased. At low doses of antigen, activation of pre-primed wild-type CD4+ T lymphocytes by WAS KO DCs in vitro was also abrogated, suggesting that there is a threshold-dependent impairment even if successful DC-T cell colocalization is achieved. Our data indicate that intrinsic DC dysfunction due to WASP deficiency directly impairs the T-cell priming response in vivo, most likely as a result of inefficient migration, but also possibly influenced by suboptimal DC-mediated cognate interaction.