Contrasting roles of PSGL-1 and PD-1 in regulating T-cell exhaustion and function during chronic viral infection.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-06 DOI:10.1128/jvi.02242-24
Karla M Viramontes, Melissa N Thone, Jamie-Jean De La Torre, Emily N Neubert, Julia M DeRogatis, Chris Garcia, Monique L Henriquez, Roberto Tinoco
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引用次数: 0

Abstract

Immune checkpoints are critical regulators of T-cell exhaustion, impairing their ability to eliminate antigens present during chronic viral infections. Current immune checkpoint inhibitors (ICIs) used in the clinic aim to reinvigorate exhausted T cells; yet, most patients fail to respond or develop resistance to these therapies, underscoring the need to better understand these immunosuppressive pathways. PSGL-1 (Selplg), a recently discovered immune checkpoint, negatively regulates T-cell function. We investigated the cell-intrinsic effects of PSGL-1, PD-1, and combined deletion on CD8+ T cells during chronic viral infection. We found that combined PSGL-1 and PD-1 (Selplg-/-Pdcd1-/-) deficiency in CD8+ T cells increased their frequencies and numbers throughout chronic infection compared to the wild type. This phenotype was primarily driven by PD-1 deficiency. Furthermore, while PD-1 deletion increased virus-specific T-cell frequencies, it was detrimental to their function. Conversely, PSGL-1 deletion improved T-cell function but resulted in lower frequencies and numbers. The primary mechanism behind these differences in cell maintenance was driven by proliferation rather than survival. Combined PSGL-1 and PD-1 deletion resulted in defective T-cell differentiation, driving cells from a progenitor self-renewal state to a more terminal dysfunctional state. These findings suggest that PD-1 and PSGL-1 have distinct, yet complementary, roles in regulating T-cell exhaustion and differentiation during chronic viral infection. Overall, this study provides novel insights into the individual and combined roles of PSGL-1 and PD-1 in CD8+ T-cell exhaustion. It underscores the potential of targeting these checkpoints in a more dynamic and sequential manner to optimize virus-specific T-cell responses, offering critical perspectives for improving therapeutic strategies aimed at reinvigorating exhausted CD8+ T cells.IMPORTANCEOur findings provide a comprehensive analysis of how the dual deletion of PD-1 and PSGL-1 impacts the response and function of virus-specific CD8+ T cells, revealing novel insights into their roles in chronic infection. Notably, our findings show that while PD-1 deletion enhances T-cell frequencies, it paradoxically reduces T-cell functionality. Conversely, PSGL-1 deletion improves T-cell function but reduces their survival. Whereas the combined deletion of PSGL-1 and PD-1 in CD8+ T cells improved their survival but decreased their function and progenitor-exhausted phenotypes during infection. We believe our study advances the understanding of immune checkpoint regulation in chronic infections and has significant implications for developing more effective immune checkpoint inhibitor (ICI) therapies.

慢性病毒感染中PSGL-1和PD-1在调节t细胞衰竭和功能中的作用对比
免疫检查点是t细胞衰竭的关键调节因子,在慢性病毒感染过程中削弱t细胞消除抗原的能力。目前用于临床的免疫检查点抑制剂(ICIs)旨在重振耗尽的T细胞;然而,大多数患者对这些疗法没有反应或产生耐药性,这强调了更好地了解这些免疫抑制途径的必要性。PSGL-1 (Selplg)是最近发现的一种免疫检查点,可负性调节t细胞功能。我们研究了慢性病毒感染期间PSGL-1、PD-1和联合缺失对CD8+ T细胞的细胞内在影响。我们发现,与野生型相比,CD8+ T细胞中PSGL-1和PD-1 (Selplg-/- pdcd1 -/-)的联合缺乏在慢性感染过程中增加了它们的频率和数量。这种表型主要是由PD-1缺乏驱动的。此外,虽然PD-1缺失增加了病毒特异性t细胞的频率,但它不利于它们的功能。相反,PSGL-1缺失改善了t细胞功能,但导致频率和数量降低。这些细胞维持差异背后的主要机制是由增殖而不是存活驱动的。PSGL-1和PD-1的联合缺失导致t细胞分化缺陷,将细胞从祖细胞自我更新状态驱动到更终端的功能失调状态。这些发现表明,PD-1和PSGL-1在慢性病毒感染期间调节t细胞衰竭和分化方面具有不同但互补的作用。总的来说,这项研究为PSGL-1和PD-1在CD8+ t细胞衰竭中的个体和联合作用提供了新的见解。它强调了以更动态和顺序的方式靶向这些检查点以优化病毒特异性T细胞反应的潜力,为改进旨在重新激活耗尽的CD8+ T细胞的治疗策略提供了关键视角。我们的研究结果全面分析了PD-1和PSGL-1的双重缺失如何影响病毒特异性CD8+ T细胞的反应和功能,揭示了它们在慢性感染中的作用。值得注意的是,我们的研究结果表明,虽然PD-1缺失增强了t细胞的频率,但矛盾的是,它降低了t细胞的功能。相反,PSGL-1的缺失改善了t细胞的功能,但降低了它们的存活率。然而,在感染期间,CD8+ T细胞中PSGL-1和PD-1的联合缺失提高了它们的存活率,但降低了它们的功能和祖细胞耗尽表型。我们相信我们的研究促进了对慢性感染免疫检查点调节的理解,并对开发更有效的免疫检查点抑制剂(ICI)疗法具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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