Dong Lulu, Sun Bijun, Min Qing, Meng Xin, Li Yaxuan, Yu Meiping, Wen Zichao, Wu Xuzhe, Hu Ziying, Zhang Runyun, Feng Xiaoqian, Luan Yingying, Lu Chunhui, Wang Wenjie, Hui Xiaoying, Hou Jia, Sun Jinqiao, Cai Shen, Wang Xiaochuan, Wang Ji-Yang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
J Clin Immunol. 2025 Aug 2;45(1):121. doi: 10.1007/s10875-025-01917-8.
The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infections due to the absence or dysfunction of T and NK cells, and nonfunctional B cells. Missense variants in the γc extracellular region are linked to atypical X-SCID with normal counts of T, B, and NK cells and less severe symptoms, yet the underlying cellular and molecular mechanisms are not well understood. This study describes a case of atypical X-SCID with a missense variant (c.420 A > T, p.R140S) in the γc extracellular domain, associated with recurrent bacterial, fungal, and viral infections. We found that the R140S variant leads to reduced surface expression and variably affects cytokine receptor signaling. Specifically, STAT5 phosphorylation and proliferation in CD4 T and CD8 T cells are impaired in response to IL-7, a cytokine essential for T cell survival, proliferation and function. Notably, γc predominantly localizes to the endoplasmic reticulum, in contrast to WT γc, which is found in acidic compartments. Despite this mislocalization, γc does not trigger unfolded protein responses, and its protein stability and degradation pathways remain unaffected. Nevertheless, cells expressing high levels of γc exhibited a competitive disadvantage in culture compared to those expressing WT γc, resulting in the enrichment of cells expressing lower levels of γc. These findings extend our understanding of how mutations in the extracellular domain of γc can lead to reduced protein expression and influence the pathophysiology of atypical X-SCID.
白细胞介素-2受体γ（IL-2Rγ，或γc）是几种细胞因子受体复合物的关键组成部分。γc缺陷导致X连锁严重联合免疫缺陷（X-SCID），其特征是由于T细胞和自然杀伤（NK）细胞缺失或功能障碍以及B细胞无功能而反复感染。γc细胞外区域的错义变异与非典型X-SCID相关，其T、B和NK细胞计数正常且症状较轻，但潜在的细胞和分子机制尚不清楚。本研究描述了一例非典型X-SCID病例，其γc细胞外结构域存在错义变异（c.420 A>T，p.R140S），与反复的细菌、真菌和病毒感染相关。我们发现R140S变异导致表面表达减少，并不同程度地影响细胞因子受体信号传导。具体而言，CD4 T细胞和CD8 T细胞中信号转导和转录激活因子5（STAT5）的磷酸化以及增殖在受到白细胞介素-7（IL-7，T细胞存活、增殖和功能所必需的细胞因子）刺激时受损。值得注意的是，与野生型（WT）γc定位于酸性区室不同，γc主要定位于内质网。尽管存在这种定位错误，γc不会引发未折叠蛋白反应，其蛋白质稳定性和降解途径也不受影响。然而，与表达WTγc的细胞相比，表达高水平γc的细胞在培养中表现出竞争劣势，导致表达较低水平γc的细胞富集。这些发现扩展了我们对γc细胞外结构域突变如何导致蛋白质表达降低并影响非典型X-SCID病理生理学的理解。
