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

• 批准号: 10559918
• 负责人: Silke Paust
• 金额: $ 26.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559918
• 关键词: Acquired Immunodeficiency Syndrome; 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; Infection prevention; Inflammatory; Investigation; Knowledge; Ligands; Ligation; Link; Lymphocyte; Mediating; Modeling; Myeloid-derived suppressor cells; Natural Killer Cells; Necrosis; Pathway interactions; Persons; Physiological; Plasma; Population; Process; Proteins; Publishing; Recombinants; Recovery; Regulatory T-Lymphocyte; Role; Serum; Stimulus; TNF gene; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Viral; 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

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。