AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Laboratory Animal Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
J Virol. 2019 Oct 15;93(21). doi: 10.1128/JVI.00896-19. Print 2019 Nov 1.
doptive ell ransfer (ACT) is a powerful experimental approach to directly study T-cell-mediated immunity In the rhesus macaque AIDS virus model, infusing simian immunodeficiency virus (SIV)-infected animals with CD8 T cells engineered to express anti-SIV T-cell receptor specificities enables direct experimentation to better understand antiviral T-cell immunity Limiting factors in ACT experiments include suboptimal trafficking to, and poor persistence in, the secondary lymphoid tissues targeted by AIDS viruses. Previously, we redirected CD8 T cells to B-cell follicles by ectopic expression of the CXCR5 homing protein. Here, we modify peripheral blood mononuclear cell (PBMC)-derived CD8 T cells to express the CCR9 chemokine receptor, which induces preferential homing of the engineered cells to the small intestine, a site of intense early AIDS virus replication and pathology in rhesus macaques. Additionally, we increase persistence and overall systemic distribution of infused CD8 T cells, especially in secondary lymphoid tissues, by minimizing culture/manipulation, thereby avoiding the loss of CD28/CD95 central memory T cells by differentiation in culture. These proof-of-principle results establish the feasibility of preferentially localizing PBMC-derived CD8 T cells to the small intestine and enables the direct experimental ACT-based assessment of the potential role of the quality and timing of effective antiviral CD8 T-cell responses to inhibit viral infection and subsequent replication in small intestine CD4 T cells. More broadly, these results support the engineered expression of homing proteins to direct CD8 T cells to target tissues as a means for both experimental and potential therapeutic advances in T-cell immunotherapies, including cancer.doptive ell ransfer (ACT) of T cells engineered with antigen-specific effector properties can deliver targeted immune responses against malignancies and infectious diseases. Current T-cell-based therapeutic ACT relies on circulatory distribution to deliver engineered T cells to their targets, an approach which has proven effective for some leukemias but provided only limited efficacy against solid tumors. Here, engineered expression of the CCR9 homing receptor redirected CD8 T cells to the small intestine in rhesus macaque ACT experiments. Targeted homing of engineered T-cell immunotherapies holds promise to increase the effectiveness of adoptively transferred cells in both experimental and clinical settings.
过继性 T 细胞转移 (ACT) 是一种强大的实验方法，可直接研究 T 细胞介导的免疫。在恒河猴艾滋病病毒模型中，给感染猴免疫缺陷病毒 (SIV) 的动物输注经过基因工程改造表达抗 SIV T 细胞受体特异性的 CD8 T 细胞，可直接进行实验以更好地理解抗病毒 T 细胞免疫。ACT 实验中的限制因素包括向艾滋病病毒靶向的次级淋巴组织中的转移不理想和持久性差。以前，我们通过异位表达趋化因子受体 5（CXCR5）归巢蛋白将 CD8 T 细胞重新导向 B 细胞滤泡。在这里，我们通过表达 CCR9 趋化因子受体将外周血单个核细胞 (PBMC) 衍生的 CD8 T 细胞进行修饰，该受体诱导工程化细胞优先归巢到小肠，这是恒河猴中艾滋病病毒复制和病理学的早期活跃部位。此外，我们通过最小化培养/操作来增加输注的 CD8 T 细胞的持久性和整体全身分布，从而避免了在培养过程中分化导致 CD28/CD95 中央记忆 T 细胞的损失。这些原理验证结果确立了将 PBMC 衍生的 CD8 T 细胞优先定位于小肠的可行性，并使直接基于 ACT 的实验评估有效抗病毒 CD8 T 细胞反应的质量和时机对抑制病毒感染和随后在小肠 CD4 T 细胞中的复制的潜在作用成为可能。更广泛地说，这些结果支持表达归巢蛋白来指导 CD8 T 细胞靶向组织，作为 T 细胞免疫疗法在实验和潜在治疗方面取得进展的一种手段，包括癌症。过继性转移具有抗原特异性效应功能的工程化 T 细胞可以针对恶性肿瘤和传染病提供靶向免疫反应。目前基于 T 细胞的治疗性 ACT 依赖于循环分布将工程化 T 细胞递送到其靶标，这种方法已被证明对某些白血病有效，但对实体瘤的疗效有限。在这里，趋化因子受体 9（CCR9）的工程表达将 CD8 T 细胞重新导向恒河猴 ACT 实验中的小肠。靶向工程化 T 细胞免疫疗法的归巢有望提高过继转移细胞在实验和临床环境中的有效性。
