Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, NY, USA.
Clin Exp Immunol. 2021 Jun;204(3):285-295. doi: 10.1111/cei.13577. Epub 2021 Feb 28.
The mechanisms that drive systemic lupus erythematosus (SLE) patients to achieve remission are unknown; one possible explanation might be T cell exhaustion. The aim of the present study was to measure CD4 and CD8 T cell exhaustion in SLE patients in prolonged remission (PR-SLE) and compared them with patients with active SLE (Act-SLE) and healthy subjects. We included 15 PR-SLE patients, 15 Act-SLE and 29 healthy subjects. T cell exhaustion was determined by flow cytometry according to the expression of programmed cell death 1 (PD)-1, T cell immunoglobulin and mucin 3 (Tim-3), natural killer cell receptor (2B4), eomesodermin (EOMES) and T-box transcription factor TBX21 (T-bet) in CD4 and CD8 T cells. Dimensionality reduction using the T-distributed stochastic neighbor-embedding algorithm and clustering analysis was used for the identification of relevant populations. Percentages of CD3 , CD4 and CD8 T cells were similar among groups. We identified five subpopulations of CD8 and seven of CD4 cells. The CD4 T-bet CD45RO cells identified in the unsupervised analysis were significantly increased in PR-SLE versus Act-SLE [median = 0·20, interquartile range (IQR) = 1·74-30·50 versus 1·68, IQR = 0·4-2·83; P < 0·01]. CD4 EOMES cells were also increased in PR-SLE versus Act-SLE (5·24, IQR = 3·38-14·70 versus 1·39, IQR = 0·48-2·87; P < 0·001). CD8 EOMES cells were increased in PR-SLE versus Act-SLE (37·6, IQR = 24·9-53·2 versus 8·13, IQR = 2·33-20·5; P < 0·001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patients versus healthy subjects. Some subpopulations of T cells expressing markers associated with exhaustion are increased in patients in remission, supporting T cell exhaustion as a tolerance mechanism in SLE. Exhaustion of specific populations of T cells might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission in these patients.
导致系统性红斑狼疮（SLE）患者达到缓解的机制尚不清楚；一种可能的解释可能是 T 细胞耗竭。本研究的目的是测量长期缓解（PR-SLE）的 SLE 患者中的 CD4 和 CD8 T 细胞耗竭，并将其与活动期 SLE（Act-SLE）患者和健康受试者进行比较。我们纳入了 15 例 PR-SLE 患者、15 例 Act-SLE 患者和 29 例健康受试者。通过流式细胞术根据程序性细胞死亡 1（PD-1）、T 细胞免疫球蛋白和粘蛋白 3（Tim-3）、自然杀伤细胞受体（2B4）、Eomesodermin（EOMES）和 T 盒转录因子 TBX21（T-bet）在 CD4 和 CD8 T 细胞中的表达来确定 T 细胞耗竭。使用 t 分布随机邻域嵌入算法进行降维和聚类分析，以识别相关群体。CD3、CD4 和 CD8 T 细胞的百分比在各组之间相似。我们鉴定了 CD8 的五个亚群和 CD4 的七个亚群。在非监督分析中鉴定的 CD4 T-bet CD45RO 细胞在 PR-SLE 中与 Act-SLE 相比显著增加[中位数=0.20，四分位距（IQR）=1.74-30.50 与 1.68，IQR=0.4-2.83；P<0.01]。PR-SLE 中 CD4 EOMES 细胞也高于 Act-SLE（5.24，IQR=3.38-14.70 与 1.39，IQR=0.48-2.87；P<0.001）。PR-SLE 中 CD8 EOMES 细胞也高于 Act-SLE（37.6，IQR=24.9-53.2 与 8.13，IQR=2.33-20.5；P<0.001）。与健康受试者相比，SLE 患者中表达与耗竭相关标志物的耗竭和活化 T 细胞的频率增加。在缓解期患者中，一些表达与耗竭相关标志物的 T 细胞亚群增加，支持 T 细胞耗竭是 SLE 中的一种耐受机制。特定 T 细胞群体的耗竭可能代表一种潜在的治疗工具，有助于实现这些患者的持续缓解。
