{"id":532,"title":"Senescent CD8 T effector memory cells are functionally impaired, enriched in aging and disease, and a barrier to immunotherapy","title_zh":"衰老型 CD8 效应记忆 T 细胞功能受损、随年龄与疾病富集，并构成免疫治疗屏障","url":"https://doi.org/10.1073/pnas.2617906123","doi":"10.1073/pnas.2617906123","pmid":null,"journal":"Proceedings of the National Academy of Sciences","kind":"paper","lang":"en","published_at":"2026-11-03T00:00:00+00:00","fetched_at":"2026-11-08T03:45:22+00:00","authors":["Paolo S. Turano","Elizabeth Akbulut","Nica M. Aquino","Luis Garza-Martínez","Sukhwinder Singh","Abraham Aviv","Simon Toupance","George S. Yap","Patricia Fitzgerald-Bocarsly","Ricardo I. Martínez-Zamudio","Utz Herbig"],"primary_topic":"repro-aging","topics":[{"slug":"repro-aging","score":5.0,"hits":["senescence","senescent"]},{"slug":"repro-immunology","score":4.0,"hits":["immunotherapy"]},{"slug":"repro-tox","score":1.0,"hits":["smoking"]},{"slug":"omics-methods","score":1.0,"hits":["single-cell rna"]}],"topic_score":5.0,"preference_score":0.0,"preference_labels":[],"llm_score":63.0,"final_score":69.0,"score_dims":{"novelty":78,"rigor":75,"impact":62,"relevance":38,"translation":42},"recommend_reason":"对免疫衰老与免疫治疗抵抗机制有较清晰的新证据（衰老独立并主导于耗竭），但研究对象为外周 CD8 T 细胞，未涉及生殖组织、胚胎或 ART 人群，与生殖医学仅为间接关联，可作为生殖免疫/生殖衰老背景阅读而非必读。","keywords":["免疫衰老","CD8 效应记忆 T 细胞","SA-βGal","T 细胞耗竭","免疫检查点阻断","单细胞转录组"],"selected":1,"story_id":111,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"pnas","journal_tier":"general-top","journal_if":9.4,"is_mock":false,"summary_zh":"该研究以人外周血 CD8 T 细胞为对象，结合单细胞 RNA 测序与功能实验，刻画表达 SA-βGal 的 CD8 效应记忆（EM）T 细胞的衰老状态。结果显示，具独特转录特征的 SA-βGal 高表达 CD8 T 细胞在各分化阶段均可出现，其 EM 亚群随增龄而增多，表达多种经典衰老标志，增殖、细胞因子分泌及清除衰老基质细胞的能力显著下降。该衰老基因特征在老年人、年龄相关疾病与肿瘤患者及吸烟者的 CD8 T 细胞中富集；且 T 细胞衰老独立于并主导于耗竭，限制 CD8 T EM 对免疫检查点阻断的应答。","summary":"Senescent cells play important roles in various biological processes that promote fitness and health; however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. In support of this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we characterized the senescence state of human SA-βGal-expressing (SA-βGal high) CD8 T effector memory (EM) cells, their functional capabilities, and their enrichment in aging and disease. Single-cell RNA sequencing revealed that SA-βGal high CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in CD8 T EM cells, which increased in abundance with human aging. SA-βGal high CD8 T EM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells. Gene signatures of senescent SA-βGal high CD8 T EM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and in smokers. Furthermore, we show that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 T EM cells to immune checkpoint blockade. Collectively, our study demonstrates that senescence impairs CD8 T EM cell function and reveals the involvement of senescent and dysfunctional CD8 T EM cells in aging, disease, smoking, and responses to immunotherapy.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}