Elahee Mehreen, Mueller Alisa A, Wang Runci, Marks Kathryne E, Sasaki Takanori, Cao Ye, Fava Andrea, Dellaripa Paul F, Boin Francesco, Rao Deepak A
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Johns Hopkins University School of Medicine, Baltimore, Maryland.
ACR Open Rheumatol. 2024 Jul;6(7):429-439. doi: 10.1002/acr2.11671. Epub 2024 May 3.
T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well-characterized cohort of patients with SSc.
Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t-distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays.
The frequencies of PD-1CXCR5 Tfh cells and PD-1CXCR5 Tph cells were similar in patients with SSc and controls. t-distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD-1CXCR5 cells distinguished by expression of HLA-DR and inducible costimulator (ICOS). Among PD-1CXCR5 cells, only the HLA-DRICOS cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA-DRICOS PD-1CXCR5 cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA-DRICOSPD-1CXCR5 cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc.
Among PD-1CXCR5 T cells, a subset of HLA-DRICOS cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.
T细胞在系统性硬化症（SSc）中导致组织损伤，但SSc患者中扩增的特定T细胞亚群仍未完全明确。在此，我们评估了与自身抗体产生有关的外周辅助性T（Tph）细胞和滤泡辅助性T（Tfh）细胞的特定表型和功能，并在一组特征明确的SSc患者队列中评估了它们与临床特征的关联。
使用t分布随机邻域嵌入可视化、双轴门控和标志物表达水平，评估SSc患者和对照者外周血单个核细胞中T细胞的质谱流式细胞术。研究结果通过流式细胞术和体外试验进行验证。
SSc患者和对照者中PD-1⁺CXCR5⁺ Tfh细胞和PD-1⁺CXCR5⁺ Tph细胞的频率相似。t分布随机邻域嵌入可视化（tSNE）显示，PD-1⁺CXCR5⁺细胞内存在不同群体，可通过HLA-DR和诱导性共刺激分子（ICOS）的表达加以区分。在PD-1⁺CXCR5⁺细胞中，只有HLA-DR⁺ICOS⁺细胞群体在SSc患者中扩增。细胞计数和RNA测序分析表明，这些细胞表达细胞毒性特征而非B细胞辅助特征。与对照T辅助细胞群体相比，HLA-DR⁺ICOS⁺ PD-1⁺CXCR5⁺细胞诱导B细胞成浆细胞分化和抗体产生的能力较弱。HLA-DR⁺ICOS⁺PD-1⁺CXCR5⁺细胞与SSc患者间质性肺疾病的存在和严重程度显著相关。
在PD-1⁺CXCR5⁺ T细胞中，具有细胞毒性特征的HLA-DR⁺ICOS⁺细胞亚群在SSc患者中特异性扩增，并与间质性肺疾病严重程度显著相关。CD4⁺ T细胞群体中出现的这种潜在细胞毒性可作为SSc患者疾病预后的生物标志物进行评估。
