Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.
Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.
复制标题
皮肤利什曼病皮肤病变的转录组学景观揭示了与免疫病理学相关的强烈 CD8 T 细胞免疫衰老特征。
DOI：
10.1111/imm.13410
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发表时间：
2021
期刊：
影响因子：
6.4
通讯作者：
Fantecelle CH
中科院分区：
文献类型：
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作者：
Fantecelle CH
巴西利什曼原虫感染患者的病变严重程度主要与高度细胞毒性和炎症性皮肤环境有关。最近，我们证明了衰老的T细胞和NK细胞在这种组织炎症的建立和维持中发挥作用。在这里，我们使用转录组学分析扩展了这些发现，证明了皮肤利什曼病（CL）病变中衰老和促炎基因特征的强烈共诱导。衰老相关的特征是关键基因如ATM、Sestrin 2、p16、p21和p38的显著表达。从大量测序数据的反褶积细胞类型鉴定表明，衰老特征与CD8+效应记忆和temrassubsets以及衰老NK细胞有关。一个关键的观察结果是，皮肤病变中的衰老标志物与患者年龄无关，并与病变大小相关。此外，衰老相关分泌表型（SASP）、促炎细胞因子和趋化因子基因的显著表达在与衰老CD8 TEMRAsubset最密切相关的病变中被发现。总的来说，我们的结果证实了在CL病变中存在衰老转录组特征，并支持了病变衰老细胞在介导该疾病的免疫病理中起主要作用的假设。
The severity of lesions that develop in patients infected byLeishmania braziliensisis mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co‐induction of senescence and pro‐inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions. The senescence‐associated signature was characterized by marked expression of key genes such as ATM, Sestrin 2, p16, p21 and p38. The cell type identification from deconvolution of bulk sequencing data showed that the senescence signature was linked with CD8+effector memory and TEMRAsubsets and also senescent NK cells. A key observation was that the senescence markers in the skin lesions are age‐independent of patients and were correlated with lesion size. Moreover, a striking expression of the senescence‐associated secretory phenotype (SASP), pro‐inflammatory cytokine and chemokines genes was found within lesions that were most strongly associated with the senescent CD8 TEMRAsubset. Collectively, our results confirm that there is a senescence transcriptomic signature in CL lesions and supports the hypothesis that lesional senescent cells have a major role in mediating immunopathology of the disease.