Artificial Antigen-Presenting Cell System Reveals CD28’s Role in modulating T-cell Functions During HIV Infection

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2024-09-13 DOI:10.1016/j.isci.2024.110947

Tayma Shaaban Kabakibo, Edwige Arnold, Kartika Padhan, Audrée Lemieux, Gloria Gabrielle Ortega-Delgado, Jean-Pierre Routy, Naglaa Shoukry, Mathieu Dubé, Daniel E. Kaufmann

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Abstract

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 elevate 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 towards TNF⍺, 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.

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人工抗原递呈细胞系统揭示 CD28 在艾滋病毒感染过程中调节 T 细胞功能的作用

T 细胞免疫功能失调是慢性 HIV 感染的一个显著特征。要评估非特异性功能障碍，需要一种同时涉及一般激活和T细胞受体（TCR）刺激的方法。我们创建了一种可调人工抗原递呈细胞（aAPC）系统。该系统由细胞测量兼容的硅微珠（5 μm）上的脂质双层膜组成。如果只加入抗 CD3，T 细胞的活化就会受到限制。引入抗 CD28 激动剂会显著提高细胞因子的表达和活化诱导标志物的上调。来自未经治疗的 HIV 感染者的 aAPC 刺激的 CD4+ 和 CD8+ T 细胞显示出效应器功能的改变和 CD28 依赖性的减弱。这些功能偏向于 TNF⍺、IFNγ 和 CD107a，IL-2 减少。抗逆转录病毒疗法能使 CD4+ T 细胞的这种扭曲特征部分恢复正常，但 CD8+ T 细胞却不能。我们的研究结果表明，T 细胞的内在偏差可能导致与 HIV 发病机制相关的持续性全身 T 细胞功能障碍。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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