CRELD1 modulates homeostasis of the immune system in mice and humans
CRELD1 modulates homeostasis of the immune system in mice and humans
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DOI：
10.1038/s41590-020-00811-2
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发表时间：
2020-11-09
影响因子：
30.5
通讯作者：
Aschenbrenner, Anna C.
中科院分区：
文献类型：
--
作者：
Bonaguro, Lorenzo;Koehne, Maren;Aschenbrenner, Anna C.
CRELD1 是心脏发育的关键因素，但其功能在成年后尚不清楚。我们在这里提供的证据表明 CRELD1 是免疫系统稳态的重要看门人。利用大型人类群体中的表达差异来对比具有最低和最高 CRELD1 表达水平的个体，揭示了强烈的表型、功能和转录差异，包括 CD4(+) T 细胞数量减少。这些发现在 T 细胞特异性 Creld1 缺陷小鼠中得到了验证。 Creld1 的缺失与同时过度激活和细胞凋亡增加有关，导致 T 细胞随着年龄的增长而净损失。 Creld1 在转录和功能上与 Wnt 信号传导相关。总的来说，大型人类群体中的基因表达差异与小鼠遗传模型、转录组学和功能测试相结合，将 CRELD1 定义为免疫稳态的重要调节剂。在人类群体中，组成型表达的蛋白质可能会发生广泛的变异。 Aschenbrenner 及其同事发现，CRELD1 表达较低的个体中幼稚 CD4(+) T 细胞的频率较低。条件性 Creld1 缺陷的小鼠也表现出与免疫衰老相关的表型。
CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4(+) T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.Within a human cohort, wide variation can occur with constitutively expressed proteins. Aschenbrenner and colleagues found that individuals with lower CRELD1 expression have decreased frequencies of naive CD4(+) T cells. Mice with conditional Creld1 deficiency also exhibit a phenotype associated with immunological aging.