Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers

IF 2.1 4区医学 Q3 IMMUNOLOGY

Human Immunology Pub Date : 2026-04-01 Epub Date: 2026-02-13 DOI:10.1016/j.humimm.2026.111687

Andreas Stephanou , Madhav Mantri , Divya Shankaranarayanan , Carol Li , Mila Lagman , Jenny Xiang , Chendong Pan , Yanjie Sun , Thangamani Muthukumar , Khaled Machaca , Iwijn De Vlaminck , Manikkam Suthanthiran

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Abstract

Store-operated calcium entry (SOCE) plays a critical role in regulating intracellular calcium signaling and is essential for immune cell functions. SOCE blockade with the pyrazole derivative BTP2 has been explored as an anti-inflammatory strategy in preclinical models, and Zegocractin (CM4620) is under clinical investigation as a CRAC channel inhibitor with activity in multiple tissues, including immune cells. However, the cell type–specific consequences of SOCE blockade under defined activation contexts remain incompletely understood. Here, we used multiplexed single-cell RNA sequencing to investigate the effects of two prototypic SOCE blockers, BTP2 and CM4620, on polyclonally stimulated, normal human peripheral blood mononuclear cells (PBMCs) in a phytohemagglutinin (PHA)-driven T-cell activation model. The data revealed that SOCE blockade suppressed cytotoxicity-associated transcriptional programs in CD8⁺ effector T cells and natural killer (NK) cells, restoring them to levels comparable to unstimulated cells. At the same time, SOCE blockade allowed CD4⁺ regulatory T cells to retain transcriptional signatures associated with immune regulation. These results indicate that, in this experimental model, SOCE blockade dampens cytotoxic programs while maintaining tolerance signatures, suggesting a potential avenue for targeted immune modulation in transplantation and other immune-mediated conditions.

Significance Statement

Store-operated calcium entry (SOCE) is essential for immune activation, but broad immunosuppression can cause significant side effects. Using single-cell transcriptomics in a phytohemagglutinin (PHA)–driven T-cell activation model, we show that SOCE blockade with BTP2 or CM4620 suppresses pro-inflammatory and cytotoxic programs in CD8⁺ effector T cells and NK cells while preserving tolerance-associated pathways in CD4⁺ regulatory T cells. These findings suggest that SOCE blockade may provide a more targeted form of immune modulation, warranting future head-to-head comparisons with conventional immunosuppressants. Our results highlight the potential of SOCE blockers to reduce immune-mediated damage while maintaining tolerance, motivating further functional and translational studies in transplantation and other immune-mediated conditions.

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单细胞转录组学揭示了SOCE阻滞剂对炎症库的靶向调节

储存操作钙进入（SOCE）在调节细胞内钙信号传导中起关键作用，对免疫细胞功能至关重要。吡唑衍生物BTP2阻断SOCE已在临床前模型中作为一种抗炎策略进行了探索，Zegocractin （CM4620）作为一种CRAC通道抑制剂正在临床研究中，在多种组织（包括免疫细胞）中具有活性。然而，在定义的激活环境下，SOCE阻断的细胞类型特异性后果仍然不完全清楚。在这里，我们使用多重单细胞RNA测序来研究两种原型SOCE阻滞剂BTP2和CM4620在植物血凝素（PHA）驱动的t细胞活化模型中对多克隆刺激的正常人外周血单核细胞（PBMCs）的影响。数据显示，SOCE阻断抑制CD8+效应T细胞和自然杀伤（NK）细胞中与细胞毒性相关的转录程序，使它们恢复到与未刺激细胞相当的水平。同时，SOCE阻断允许CD4+调节性T细胞保留与免疫调节相关的转录特征。这些结果表明，在这个实验模型中，SOCE阻断抑制了细胞毒性程序，同时保持了耐受性特征，这表明在移植和其他免疫介导的疾病中靶向免疫调节的潜在途径。存储操作的钙进入（SOCE）是免疫激活所必需的，但广泛的免疫抑制可能导致显著的副作用。在植物血凝素（PHA）驱动的T细胞激活模型中使用单细胞转录组学，我们发现BTP2或CM4620阻断SOCE可以抑制CD8+效应T细胞和NK细胞中的促炎和细胞毒性程序，同时保留CD4+调节性T细胞中的耐受性相关途径。这些发现表明，SOCE阻断可能提供一种更有针对性的免疫调节形式，保证未来与传统免疫抑制剂进行正面比较。我们的研究结果强调了SOCE阻滞剂在维持耐受性的同时减少免疫介导的损伤的潜力，推动了移植和其他免疫介导疾病的进一步功能和转化研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Immunology 医学-免疫学

CiteScore

5.40

自引率

7.40%

发文量

107

审稿时长

12 days

期刊介绍： The journal''s scope includes understanding the genetic and functional mechanisms that distinguish human individuals in their immune responses to allografts, pregnancy, infections or vaccines as well as the immune responses that lead to autoimmunity, allergy or drug hypersensitivity. It also includes examining the distribution of the genes controlling these responses in populations. Research areas include: Studies of the genetics, genomics, polymorphism, evolution, and population distribution of immune-related genes Studies of the expression, structure and function of the products of immune-related genes Immunogenetics of susceptibility to infectious and autoimmune disease, and allergy The role of the immune-related genes in hematopoietic stem cell, solid organ, and vascularized composite allograft transplant Histocompatibility studies including alloantibodies, epitope definition, and T cell alloreactivity Studies of immunologic tolerance and pregnancy T cell, B cell, NK and regulatory cell functions, particularly related to subjects within the journal''s scope Pharmacogenomics and vaccine development in the context of immune-related genes Human Immunology considers immune-related genes to include those encoding classical and non-classical HLA, KIR, MIC, minor histocompatibility antigens (mHAg), immunoglobulins, TCR, BCR, proteins involved in antigen processing and presentation, complement, Fc receptors, chemokines and cytokines. Other immune-related genes may be considered. Human Immunology is also interested in bioinformatics of immune-related genes and organizational topics impacting laboratory processes, organ allocation, clinical strategies, and registries related to autoimmunity and transplantation.