Peng Ting, Fang Qing, Zhao Zihao, Chang Yingjun, Zhao Xiangyu, Li Cheng
School of Life Sciences, Peking University, Beijing, China.
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
Clin Transl Med. 2025 Aug;15(8):e70430. doi: 10.1002/ctm2.70430.
Naïve T cells are maintained in a quiescent state prior to activation. As inappropriate T-cell activation can lead to impaired immune tolerance and autoimmune diseases, the transition from quiescence to activation must be under strict regulation. Despite its importance, the mechanisms underlying the maintenance of the quiescent state remain incompletely understood.
Through multi-omics integration analysis, we reveal that INPP4B, a phosphatase of the phosphoinositide 3-kinase pathway, is highly expressed specifically in T cells and is involved in suppressing T-cell activation and maintaining quiescence. Our findings uncover that INPP4B forms a T-cell-specific chromatin interaction domain and exhibits high expression levels in quiescent T cells. Upon T-cell activation, both the chromatin interaction and expression levels of INPP4B decrease. Functional studies further confirm that INPP4B suppresses T-cell activation and effector functions. Additionally, we observe increased expression level of INPP4B in exhausted T cells within the tumour microenvironment.
These results highlight the importance of maintaining optimal levels of INPP4B for T-cell function. Our findings suggest that INPP4B could be a potential target for enhancing the efficacy of T-cell-mediated immune responses against tumours.
A comprehensive multi-omics analysis characterizes the expression patterns of INPP4B across immune populations. INPP4B exhibits a T-cell-specific expression domain and functions as a T cell activation suppressor. INPP4B is significantly upregulated in exhausted T cells within the tumour microenvironment.
初始T细胞在激活前维持在静止状态。由于不适当的T细胞激活会导致免疫耐受受损和自身免疫性疾病，从静止到激活的转变必须受到严格调控。尽管其很重要，但静止状态维持的潜在机制仍未完全了解。
通过多组学整合分析，我们发现肌醇多磷酸4-磷酸酶B（INPP4B），一种磷脂酰肌醇3-激酶途径的磷酸酶，在T细胞中特异性高表达，并参与抑制T细胞激活和维持静止状态。我们的研究结果揭示，INPP4B形成一个T细胞特异性染色质相互作用结构域，并在静止T细胞中表现出高表达水平。在T细胞激活时，INPP4B的染色质相互作用和表达水平均降低。功能研究进一步证实，INPP4B抑制T细胞激活和效应功能。此外，我们观察到肿瘤微环境中耗竭T细胞中INPP4B的表达水平增加。
这些结果突出了维持INPP4B最佳水平对T细胞功能的重要性。我们的研究结果表明，INPP4B可能是增强T细胞介导的抗肿瘤免疫反应疗效的潜在靶点。
全面的多组学分析表征了INPP4B在免疫群体中的表达模式。INPP4B表现出T细胞特异性表达结构域，并作为T细胞激活抑制剂发挥作用。INPP4B在肿瘤微环境中的耗竭T细胞中显著上调。
