Sun Yumeng, Sen Subha, Parmar Rajesh, Arakawa-Hoyt Janice, Cappelletti Monica, Rossetti Maura, Gjertson David W, Sigdel Tara K, Sarwal Minnie M, Schaenman Joanna M, Bunnapradist Suphamai, Lanier Lewis L, Pickering Harry, Reed Elaine F
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, United States.
Front Immunol. 2025 Feb 14;16:1542531. doi: 10.3389/fimmu.2025.1542531. eCollection 2025.
Cytomegalovirus (CMV) viremia remains a major contributor to clinical complications in solid organ transplant (SOT) patients, including organ injury, morbidity and mortality. Given their critical role in antiviral defense, CD8+ T cells are essential for protective immunity against CMV.
Using single-cell RNA sequencing, we investigated the transcriptional signatures and developmental lineages of CD8+ T cells in eight immunosuppressed kidney transplant recipients (KTRs) who received organs from CMV-seropositive donors. Results were validated in a cohort of 62 KTRs using immunophenotyping.
Our data revealed a significant influence of CMV serostatus on transcriptional variance of CD8+ memory T cells, associating with the first principal component from a global analysis of CD8+ T cells (p =0.0406), forming a continuum with five principal differentiation trajectories driven by CMV primary infection or reactivation. Following CMV primary infection, CD8+ T cells were hallmarked by restrained effector-memory differentiation. CD8+ T cells during CMV reactivation diverged non-linearly into senescent-like cells with signatures of arrested cell cycle, diminished translational activity and downregulated and longitudinally expanding effector cells with robust cytotoxic potential and upregulated , acting as a reservoir for long-lived effector cells supporting long-term protection. Notably, CD28 KLRG1 IL-7R (CD127) HLA-DR CD8+ T cells present prior to the detection of viremia in CMV-seropositive patients emerged as a key feature distinguishing patients who did or did not undergo CMV reactivation after prophylaxis discontinuation (p =0.0163). Frequencies of these cells were also positively correlated with CMV-stimulated secretion of IFN-γ (p =0.0494), TNF-α (p =0.0358), MIP-1α (p =0.0262), MIP-1β (p =0.0043).
These results provide insights into the transcriptional regulation that influences the generation of CD8+ T cell immunity to CMV and may inform strategics for monitoring host immune response to CMV to better identify and introduce therapeutic intervention to patients at risk of developing clinically significant CMV viremia.
巨细胞病毒（CMV）血症仍然是实体器官移植（SOT）患者临床并发症的主要促成因素，包括器官损伤、发病率和死亡率。鉴于其在抗病毒防御中的关键作用，CD8 + T细胞对于针对CMV的保护性免疫至关重要。
我们使用单细胞RNA测序，研究了8名接受来自CMV血清反应阳性供体器官的免疫抑制肾移植受者（KTR）中CD8 + T细胞的转录特征和发育谱系。使用免疫表型分析在一组62名KTR中验证了结果。
我们的数据揭示了CMV血清状态对CD8 + 记忆T细胞转录变异的显著影响，与对CD8 + T细胞的全局分析中的第一主成分相关（p = 0.0406），形成了由CMV原发性感染或再激活驱动的五条主要分化轨迹的连续体。在CMV原发性感染后，CD8 + T细胞的特征是效应记忆分化受到抑制。CMV再激活期间的CD8 + T细胞非线性地分化为具有细胞周期停滞、翻译活性降低和下调特征的衰老样细胞，以及具有强大细胞毒性潜力和上调的纵向扩增效应细胞，作为支持长期保护的长寿效应细胞的储存库。值得注意的是，在CMV血清反应阳性患者中检测到病毒血症之前出现的CD28 KLRG1 IL - 7R（CD127）HLA - DR CD8 + T细胞成为区分预防措施停止后是否经历CMV再激活的患者的关键特征（p = 0.0163）。这些细胞的频率也与CMV刺激的IFN - γ（p = 0.0494）、TNF - α（p = 0.0358）、MIP - 1α（p = 0.0262）、MIP - 1β（p = 0.0043）分泌呈正相关。
这些结果为影响针对CMV的CD8 + T细胞免疫产生的转录调控提供了见解，并可能为监测宿主对CMV的免疫反应以更好地识别并对有发生临床显著CMV血症风险的患者引入治疗干预的策略提供信息。
