Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, Paris, France.
J Clin Invest. 2024 Oct 1;134(19):e180251. doi: 10.1172/JCI180251.
Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
患有双等位基因 IL7R 功能丧失变异的婴儿患有严重联合免疫缺陷 (SCID)，其特征是缺乏自体 T 淋巴细胞，但循环 B 和 NK 细胞 (T-B+NK+SCID) 计数正常。我们报告了来自 4 个家系和 3 个祖系（哥伦比亚、以色列阿拉伯、日本）的 6 名成年人（年龄 22 至 59 岁），他们携带纯合性 IL7 功能丧失变异导致联合免疫缺陷 (CID)。深度免疫表型显示髓样细胞、B 细胞、NK 细胞和固有淋巴样细胞的计数和/或比例相对正常。相比之下，患者存在严重的 T 细胞淋巴细胞减少症，固有样适应性黏膜相关不变 T 和不变自然杀伤 T 细胞的比例较低。他们的 T 细胞受体 (TCR) 切除环、近期胸腺移民 T 细胞和幼稚 CD4+T 细胞的血液计数也较低，整体 TCR repertoire 多样性较低，这表明胸腺输出受损。效应记忆 CD4+和 CD8+T 细胞的比例较高，表明 IL-7 非依赖性外周稳态 T 细胞增殖。有趣的是，其他 T 细胞亚群的比例，包括 TCRγδ+T 细胞和一些 TCRαβ+T 细胞亚群（包括 Th1、Tfh 和 Treg）受影响较小。外周 CD4+T 细胞增殖能力差，但体外刺激有丝分裂原时细胞因子产生正常。因此，与 IL-7R 缺乏相比，遗传性 IL-7 缺乏对 T 细胞发育的影响较轻且更具亚群特异性。这些发现表明，另一种 IL-7R 结合细胞因子，可能是胸腺基质淋巴细胞生成素，调控人类 T 细胞发育的 IL-7 非依赖性途径。
