Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection.
Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection.
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DOI：
10.3389/fimmu.2021.608890
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发表时间：
2021
影响因子：
7.3
通讯作者：
Jain P
中科院分区：
文献类型：
--
作者：
Clements DM;Crumley B;Chew GM;Davis E;Bruhn R;Murphy EL;Ndhlovu LC;Jain P
人类 T 细胞淋巴细胞病毒 1 型 (HTLV-1) 相关性脊髓病/热带痉挛性截瘫 (HAM/TSP) 在 1-5% 的 HTLV-1 感染者中发生。我们和其他人之前的研究表明，在各种慢性病毒感染中，CD8 T 细胞上阴性免疫检查点受体 (NCR) 的表达显着增加，并且与抗病毒免疫力差有关。我们之前已经确定了 HAM/TSP 患者血液和 HTLV-1 感染人源化小鼠中枢神经系统 (CNS) 组织中 CD8 T 细胞上 NCR 的差异表达，并确定了与神经系统并发症的关联。在这项研究中，我们确定了 HTLV-1 感染中几个关键 NCR（PD-1、TIGIT、TIM-3 和 LAG-3）及其同源配体的共表达模式，并评估了针对这些途径的组合策略如何影响 HTLV-1 特异性 CD8 T 细胞效应器功能，作为减少 CNS 疾病结果的方法。我们发现，HAM/TSP 患者的整体 CD8 T 细胞共表达多个 NCR 的频率明显高于无症状携带者 (AC)。此外，与 AC 相比，HAM/TSP 中浆细胞和髓系树突细胞上的 NCR 配体（PVR 和 PD-LI）也以更高的频率表达。在 AC 和 HAM/TSP 受试者中，双重 PD-L1/TIGIT 或三重 PD-L1/TIGIT/TIM-3 阻断与单克隆抗体的组合导致病毒刺激后 CD8 T 细胞中细胞内细胞因子表达增加，特别是脱颗粒标记物 CD107a 和可直接抑制病毒复制的关键细胞因子 TNF-α。有趣的是，几乎所有阻断组合都会导致 HAM/TSP 受试者中 IL-2+ HTLV-1 特异性 CD8 T 细胞频率降低，但在 AC 中则不然。这些结果定义了一种新的组合 NCR 免疫治疗阻断策略，以减轻 HAM/TSP 疾病负担。
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1–5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.
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DOI：
10.4049/jimmunol.1000841
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mackerness KJ;Cox MA;Lilly LM;Weaver CT;Harrington LE;Zajac AJ
通讯作者：
Zajac AJ
影响因子：
9.1
作者：
Manuel SL;Sehgal M;Connolly J;Makedonas G;Khan ZK;Gardner J;Betts MR;Jain P
通讯作者：
Jain P
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.4
作者：
Abdelbary, Nashwa H.;Abdullah, Hazem M.;Kubota, Ryuji
通讯作者：
Kubota, Ryuji
并非所有免疫检查点都是相等的。
影响因子：
7.3
作者：
De Sousa Linhares A;Leitner J;Grabmeier-Pfistershammer K;Steinberger P
通讯作者：
Steinberger P