Lpar5 regulates the CD8 T-cell response to persistent virus infection by altering exhaustion programming, survival, and NK receptor expression.

IF 3.4 3区 医学 Q2 IMMUNOLOGY
Marc A D'Antonio, Brian C Ware, James E DiLisio, Mary Jessamine Michaels, Jacqueline A Turner, Lauren M Habenicht, Bennett J Davenport, Thomas E Morrison, Roberta Pelanda, Laurent Gapin, Raul M Torres
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Abstract

Persistent antigen exposure during chronic viral infection and tumor development drives CD8 T cells into an exhausted, hypofunctional state. Understanding the molecular pathways that enforce T-cell exhaustion is critical for improving current immunotherapies. Previously, we have shown the bioactive lipid lysophosphatidic acid (LPA) regulates CD8 T-cell function through LPA receptor 5 (LPAR5) signaling, including demonstrating that Lpar5-/- CD8 T cells exhibit enhanced tumor clearance in murine models of melanoma. Importantly, significantly elevated levels of LPA have been identified in individuals with different cancers and persistent viral infections such as HIV, hepatitis C virus, and hepatitis B virus. To investigate the role of Lpar5 in the differentiation and maintenance of exhausted CD8 T cells, we utilized the lymphocytic choriomeningitis virus (LCMV) infection model. In response to infection with LCMV Clone 13, but not Armstrong, one-quarter of Lpar5-/- animals succumbed to infection, and this was accompanied by an increased frequency of LCMV-specific Lpar5-/- CD8 T cells maintained in a less terminally exhausted state. Using P14 transgenic mice, we demonstrate that Lpar5 acts in a cell-intrinsic and temporal manner to regulate CD8 T-cell accumulation and exhaustion programming during Clone 13 infection. The enhanced accumulation of Lpar5-/- P14 cells during the acute phase of Clone 13 infection appears to be regulated by Lpar5-mediated changes in T-cell survival and not through trafficking or proliferation. RNA sequencing analyses and surface phenotyping show that Lpar5 likely regulates CD8 T-cell exhaustion through modulation of NK receptor expression, including the CD94/NKG2A inhibitory axis.

Lpar5通过改变耗尽程序、存活和NK受体表达来调节CD8 t细胞对持续病毒感染的反应。
在慢性病毒感染和肿瘤发展过程中,持续的抗原暴露会使CD8 T细胞进入衰竭、功能低下的状态。了解强制t细胞耗竭的分子途径对于改进当前的免疫疗法至关重要。之前,我们已经证明了生物活性脂质溶血磷脂酸(LPA)通过LPA受体5 (LPAR5)信号传导调节CD8 T细胞的功能,包括证明LPAR5 -/- CD8 T细胞在小鼠黑色素瘤模型中表现出增强的肿瘤清除能力。重要的是,在患有不同癌症和持续性病毒感染(如HIV、丙型肝炎病毒和乙型肝炎病毒)的个体中发现了显著升高的LPA水平。为了研究Lpar5在耗尽的CD8 T细胞分化和维持中的作用,我们利用淋巴细胞性脉络丛脑膜炎病毒(LCMV)感染模型。在LCMV克隆13(而不是Armstrong)感染的反应中,四分之一的Lpar5-/-动物死于感染,这伴随着LCMV特异性Lpar5-/- CD8 T细胞维持在较少的终端耗尽状态的频率增加。使用P14转基因小鼠,我们证明Lpar5以细胞内在和时间的方式调节克隆13感染期间CD8 t细胞的积累和耗竭编程。在克隆13感染的急性期,Lpar5-/- P14细胞的增强积累似乎是由Lpar5介导的t细胞存活变化调节的,而不是通过运输或增殖。RNA测序分析和表面表型分析表明,Lpar5可能通过调节NK受体表达(包括CD94/NKG2A抑制轴)来调节CD8 t细胞耗竭。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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