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.

CRELD1是心脏发育的关键因素，其功能在成人生活中是未知的。我们在这里提供证据，表明CRELD1是免疫系统稳态的重要守门人。在具有最低和最高CRELD1表达水平的个体形成对比的大型人类群体中，利用表达差异揭示出强大的表型，功能和转录差异，包括减少的CD4 ⁺ T细胞数量。这些发现在T细胞特异性Creld1缺陷小鼠中得到了验证。Creld1的丧失与同时过度激活和凋亡增加有关，导致T细胞随着年龄的增长而净丧失。Creld1在转录和功能上与Wnt信号传导相关。总的来说，在大型人类队列中的基因表达差异与鼠类遗传模型，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。