Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes

细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制

基本信息

批准号：
10674910
负责人：
Silke Paust
金额：
$ 3.54万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-08-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674910
关键词：
Acquired Immunodeficiency Syndrome Activated Natural Killer Cell Animals Apoptosis CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell surface Cells Cessation of life Cytotoxic T-Lymphocytes Data Disease Frequencies Future HIV HIV Infections Human Immune Immune System Diseases Immune system Immunosuppression Immunotherapy In Vitro Incidence Induction of Apoptosis Infection prevention Inflammatory Investigation Knowledge Ligands Ligation Link Lymphocyte Lymphocyte Depletion Mediating Modeling Myeloid-derived suppressor cells Natural Killer Cells Pathway interactions Persons Physiological Plasma Population Predisposition Process Proteins Publishing Recombinants Recovery Regulatory T-Lymphocyte Role Serum Stimulus TNF gene TNFRSF10A gene TNFRSF10B gene Testing Therapeutic Viral Viral Physiology Work antiretroviral therapy cancer immunotherapy cell killing cell type cytotoxic granulocyte immune checkpoint immune checkpoint blockade improved in vivo insight monocyte mouse model neutrophil novel peripheral blood prevent receptor tool

项目摘要

Elevated frequencies of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) precede and contribute to immune dysfunction in persons living with HIV (PLHIV). The underlying mechanisms of this dysregulation are poorly understood. Potential mechanisms under investigation include PMN-MDSCs impacting CD4+ T cell recovery, expanding T-regulatory cells (T-reg), inducing immune checkpoints (IC), and suppressing the antiviral functions of cytotoxic lymphocytes. While the initiation of combined antiretroviral therapy (cART) can reduce peripheral blood PMN-MDSCs levels in PLHIV, PMN-MDSCs levels can remain elevated despite cART, and cART does not remedy all PMN-MDSC-induced immune dysfunction. The tumor-necrosis-factor-related- apoptosis-inducing-ligand (TRAIL) is a cell-surface and secreted apoptosis-inducing protein expressed by activated human Natural Killer (NK) cells and cytotoxic T lymphocytes (CD8+ T cells, CTL). TRAIL ligation of its receptors (also called death receptors (DRs)) induces apoptosis on DR-expressing cells. PMN-MDSCs express TRAIL-R1 (DR4) and 2 (DR5). Recently published work showed a link between serum levels of agonistic soluble TRAIL (sTRAIL) and PMN-MDSC frequency in PLHIV. Early in HIV infection, PMN-MDSC frequency inversely correlates with plasma levels of sTRAIL, and recombinant TRAIL induces PMN-MDSC apoptosis in vitro. Thus, DR ligation, currently being explored as an immunotherapy for cancer, may be a way to reduce PMN-MDSCs frequencies in PLHIV. In addition to TRAIL, PMN-MDSCs also express NKG2D-ligands. NKG2D is an NK cell activating receptor and a positive costimulatory receptor of human CTLs, and NKG2D-ligand expression renders PMN-MDSCs highly susceptible to NK cell killing. However, despite data implicating PMN-MDSCs as essential contributors to immune dysfunction and HIV disease, approaches targeting PMN-MDSCs in PLHIV have yet to be explored. Using a mouse model with a competent and HIV susceptible humanized immune system, we found that PMN-MDSCs expand rapidly upon HIV infection. Like in humans, PMN-MDSCs correlated positively with HIV viral titers and T-reg in this model. Mechanistic studies in cytotoxic lymphocyte-depleted animals revealed that NK cells and perhaps also CTLs controlled PMN-MDSC expansion, expressed NKG2D, and upregulated TRAIL upon HIV infection. We propose to explore the mechanisms by which PMN-MDSC and consequent Treg expansions are controlled. We propose to test the hypothesis that therapeutic PMN-MDSCs reduction during HIV infection prevents PMN-MDSCs-caused immune dysfunction, improving viral control. Our studies will leverage novel tools and therapeutic approaches to define the impact of the TRAIL and NKG2D pathways on controlling PMN-MDSC and resultant Treg expansion upon HIV infection. We will explore therapeutic strategies to reduce PMN-MDSC and prevent T-reg expansion upon HIV infection in vivo. The knowledge gained from our work will facilitate new insight into the mechanisms that control or exacerbate HIV-infection-induced immune disturbance and disease.

在患有艾滋病毒（PLHIV）的人的免疫功能障碍。这种失调的基本机制是理解不佳。正在研究的潜在机制包括影响CD4+ T细胞的PMN-MDSC 恢复，扩大T调节细胞（T-REG），诱导免疫检查点（IC）并抑制抗病毒细胞毒性淋巴细胞的功能。虽然抗逆转录病毒疗法（CART）的启动可以减少 PLHIV中的外周血PMN-MDSC水平，尽管购物车，PMN-MDSCS水平仍然可以升高，并且购物车不能补救所有PMN-MDSC诱导的免疫功能障碍。肿瘤因素因素相关 - 凋亡 - 诱导 - 配体（TRAR）是一种细胞表面和分泌凋亡的诱导蛋白，由活化的人类天然杀伤（NK）细胞和细胞毒性T淋巴细胞（CD8+ T细胞，CTL）。踪迹受体（也称为死亡受体（DRS））诱导表达DR的细胞凋亡。 PMN-MDSCS Express TRAIL-R1（DR4）和2（DR5）。最近发表的工作显示了激动性可溶性水平之间的联系 PLHIV中的TRAIL（Strail）和PMN-MDSC频率。在HIV感染的早期，PMN-MDSC频率成反比与血浆水平的水平相关，重组小径在体外诱导PMN-MDSC凋亡。因此，目前正在作为癌症免疫疗法探索的连接博士可能是减少PMN-MDSC的一种方法 PLHIV中的频率。除TRAIL外，PMN-MDSC还表达NKG2D-Ligands。 NKG2D是一个NK单元人CTL的激活受体和阳性共刺激受体和NKG2D-cligand表达渲染 PMN-MDSC非常容易受到NK细胞杀伤的影响。然而，尽管数据将PMN-MDSC视为必不可少免疫功能障碍和HIV疾病的贡献者，针对PLHIV的PMN-MDSC的方法尚未被探索。使用具有胜任和艾滋病毒易感的人源性免疫系统的鼠标模型，我们发现 PMN-MDSC在HIV感染后迅速扩展。与人类一样，PMN-MDSC与此模型中的HIV病毒滴和T-REG。细胞毒性淋巴细胞的动物的机械研究显示 NK细胞以及CTL也控制了PMN-MDSC扩展，表达了NKG2D，并上调在艾滋病毒感染时进行踪迹。我们建议探索PMN-MDSC和随之而来的Treg的机制扩展是控制的。我们建议检验以下假设： HIV感染可防止PMN-MDSC引起的免疫功能障碍，从而改善病毒控制。我们的研究将利用新颖的工具和治疗方法来定义步道和NKG2D途径的影响在HIV感染后控制PMN-MDSC和由此导致的Treg扩张。我们将探索治疗策略减少PMN-MDSC并防止在体内HIV感染后T-REG扩张。从我们那里获得的知识工作将促进对控制或加剧HIV感染诱导的免疫的机制的新见解干扰和疾病。