Kabakibo Tayma Shaaban, Arnold Edwige, Padhan Kartika, Lemieux Audrée, Ortega-Delgado Gloria Gabrielle, Routy Jean-Pierre, Shoukry Naglaa, Dubé Mathieu, Kaufmann Daniel E
Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
Université de Montréal, Montréal, QC, Canada.
iScience. 2024 Sep 13;27(10):110947. doi: 10.1016/j.isci.2024.110947. eCollection 2024 Oct 18.
T cell immune dysfunction is a prominent feature of chronic HIV infection. To evaluate non-specific dysfunction, a method involving both generic activation and T cell receptor (TCR) stimulation is necessary. We created a tunable artificial antigen-presenting cell (aAPC) system. This system consists of lipid bilayers on cytometry-compatible silica microbeads (5 μm). When only anti-CD3 is incorporated, T cell activation is limited. Introducing anti-CD28 agonists significantly elevates the cytokine expression and upregulation of activation-induced markers. CD28 co-stimulation modulates the response profile, preferentially promoting IL-2 expression relative to other cytokines. aAPCs-stimulated CD4 and CD8 T cells from untreated HIV-infected individuals exhibit altered effector functions and diminished CD28 dependence. These functions are skewed toward TNFα, IFNγ and CD107a, with reduced IL-2. Antiretroviral therapy partially normalizes this distorted profile in CD4 T cells, but not in CD8 T cells. Our findings show T cell intrinsic biases that may contribute to persistent systemic T cell dysfunction associated with HIV pathogenesis.
T细胞免疫功能障碍是慢性HIV感染的一个突出特征。为了评估非特异性功能障碍，需要一种涉及通用激活和T细胞受体（TCR）刺激的方法。我们创建了一种可调谐的人工抗原呈递细胞（aAPC）系统。该系统由与细胞计数兼容的二氧化硅微珠（5μm）上的脂质双层组成。当仅掺入抗CD3时，T细胞激活受到限制。引入抗CD28激动剂可显著提高细胞因子表达和激活诱导标志物的上调。CD28共刺激调节反应谱，相对于其他细胞因子优先促进IL-2表达。来自未接受治疗的HIV感染个体的aAPC刺激的CD4和CD8 T细胞表现出效应功能改变和对CD28依赖性降低。这些功能偏向于TNFα、IFNγ和CD107a，而IL-2减少。抗逆转录病毒疗法部分使CD4 T细胞中这种扭曲的谱正常化，但对CD8 T细胞无效。我们的研究结果显示了T细胞内在的偏差，这可能导致与HIV发病机制相关的持续性全身T细胞功能障碍。
