Long Huizhong, Espinosa Luis, Sawalha Amr H
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
J Autoimmun. 2024 Dec;149:103324. doi: 10.1016/j.jaut.2024.103324. Epub 2024 Oct 13.
Hydroxychloroquine (HCQ) is widely used in the treatment of a variety of autoimmune diseases. However, the mechanisms responsible for the immunomodulatory properties of HCQ in T cells remain unclear. Here we used single-cell RNA-sequencing to examine the effect of HCQ on T cells following in vitro stimulation. HCQ treatment led to a reduction in effector CD4 T cells and upregulation of inhibitory genes including CTLA4 and TNFAIP3 in effector and naive CD4 T cells, respectively. HCQ induced a significant expansion of effector CD8 T cells, and significantly upregulated key cytotoxicity genes including GZMA, GZMB, GZMH, KLRD1, NKG7, and PRF1, as well as IFNG expression. Furthermore, HCQ treatment led to a reduction in the CD38 CD8 T cell subset, which is characterized by defective cytotoxicity and thought to both play a pathogenic role and increase susceptibility to infections in autoimmunity. We analyzed single-cell RNA-sequencing data in effector CD8 T cells from lupus patients with or without HCQ treatment and confirmed upregulation of key cytotoxicity genes in patients receiving HCQ. In conclusion, this work provides additional insights into the immunomodulatory effects of HCQ and indicates that HCQ improves T cell cytotoxicity, which could explain a previously suggested protective effect of HCQ against infections in patients with autoimmune diseases.
羟氯喹（HCQ）广泛用于治疗多种自身免疫性疾病。然而，HCQ在T细胞中的免疫调节特性的作用机制仍不清楚。在这里，我们使用单细胞RNA测序来研究体外刺激后HCQ对T细胞的影响。HCQ处理导致效应CD4 T细胞减少，并且分别在效应和初始CD4 T细胞中上调包括CTLA4和TNFAIP3在内的抑制基因。HCQ诱导效应CD8 T细胞显著扩增，并显著上调关键的细胞毒性基因，包括GZMA、GZMB、GZMH、KLRD1、NKG7和PRF1，以及IFNG表达。此外，HCQ处理导致CD38 CD8 T细胞亚群减少，该亚群以细胞毒性缺陷为特征，被认为在自身免疫中既起致病作用又增加感染易感性。我们分析了接受或未接受HCQ治疗的狼疮患者效应CD8 T细胞中的单细胞RNA测序数据，并证实接受HCQ治疗的患者中关键细胞毒性基因上调。总之，这项工作为HCQ的免疫调节作用提供了更多见解，并表明HCQ改善T细胞细胞毒性，这可以解释先前提出的HCQ对自身免疫性疾病患者感染的保护作用。
