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.

粒细胞髓源性抑制细胞 (PMN-MDSC) 频率升高先于并促成艾滋病毒感染者（PLHIV）的免疫功能障碍。这种失调的根本机制是不太了解。正在研究的潜在机制包括 PMN-MDSC 影响 CD4+ T 细胞恢复、扩大 T 调节细胞 (T-reg)、诱导免疫检查点 (IC) 以及抑制抗病毒细胞毒性淋巴细胞的功能。虽然开始联合抗逆转录病毒治疗（cART）可以减少 PLHIV 患者外周血 PMN-MDSC 水平，尽管进行了 cART，PMN-MDSC 水平仍可保持升高，并且 cART 不能治愈所有 PMN-MDSC 引起的免疫功能障碍。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 是一种细胞表面分泌的凋亡诱导蛋白，由激活的人类自然杀伤 (NK) 细胞和细胞毒性 T 淋巴细胞（CD8+ T 细胞，CTL）。其 TRAIL 连接受体（也称为死亡受体 (DR)）诱导 DR 表达细胞凋亡。 PMN-MDSC表达 TRAIL-R1 (DR4) 和 2 (DR5)。最近发表的研究表明，激动性可溶性血清水平之间存在联系。 PLHIV 中的 TRAIL (sTRAIL) 和 PMN-MDSC 频率。 HIV感染早期，PMN-MDSC频率呈反比与血浆 sTRAIL 水平相关，重组 TRAIL 在体外诱导 PMN-MDSC 凋亡。因此，目前正在探索将 DR 连接作为一种癌症免疫疗法，可能是减少 PMN-MDSC 的一种方法 PLHIV 中的频率。除了 TRAIL 之外，PMN-MDSC 还表达 NKG2D 配体。 NKG2D 是一种 NK 细胞激活受体和人类 CTL 的正共刺激受体，以及 NKG2D 配体表达使得 PMN-MDSC 对 NK 细胞杀伤高度敏感。然而，尽管数据表明 PMN-MDSC 至关重要 PMN-MDSCs 是导致免疫功能障碍和 HIV 疾病的重要因素，针对 PLHIV 中的 PMN-MDSCs 的治疗方法尚未得到证实。被探索。使用具有强大且易受艾滋病毒影响的人源化免疫系统的小鼠模型，我们发现 PMN-MDSC 在 HIV 感染后迅速扩增。与人类一样，PMN-MDSCs 与该模型中的 HIV 病毒滴度和 T-reg。细胞毒性淋巴细胞耗尽动物的机制研究揭示 NK 细胞或许还有 CTL 控制 PMN-MDSC 扩增、表达 NKG2D 并上调 HIV 感染后的 TRAIL。我们建议探索 PMN-MDSC 和随后的 Treg 的机制扩张受到控制。我们建议检验以下假设：治疗期间 PMN-MDSC 减少 HIV 感染可预防 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的工具和治疗方法来定义 TRAIL 和 NKG2D 通路对控制 PMN-MDSC 和 HIV 感染后 Treg 的扩增。我们将探讨治疗策略减少 PMN-MDSC 并防止 HIV 感染体内 T-reg 扩增。从我们获得的知识这项工作将促进对控制或加剧艾滋病毒感染诱导的免疫机制的新见解干扰和疾病。