Mueller April L, Lamcaj Sara, Garforth Scott, Hiner Christopher, Woodley Darien, Paraiso Kitt, Mi Tian, Low Simon, Youngblood Ben, Almo Steven C, Goldstein Harris
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
J Virol. 2025 Aug 5:e0018825. doi: 10.1128/jvi.00188-25.
UNLABELLED: Adoptive cell transfer (ACT), a promising immunotherapeutic approach, treats viral infections or cancer by expansion and infusion of antigen-specific CD8+ T cells, respectively. However, its wider use is limited by logistical challenges associated with the conventional method of using patient-derived dendritic cells (DCs) loaded with peptides for antigen-specific CD8+ T cell expansion. To overcome these limitations, we developed Immuno-STAT (IST), a dimeric protein scaffold that delivers peptide-specific T cell receptor (TCR) activation with or without CD28 costimulatory signals to expand CD8+ T cells specific for defined viral or cancer epitopes. In this proof-of-concept study, we demonstrate that anti-CD28-IST can selectively activate and expand polyfunctional cytotoxic CD8+ T cells from the naive repertoire, targeting the HIV-associated SL9 or melanoma-associated MART-1 epitopes. Naive MART-1-specific CD8+ T cells were reliably expanded by both peptide-loaded DCs and IST. In contrast, naive SL9-specific CD8+ T cells were expanded only by SL9-specific IST and not by conventional DC-based approaches, underscoring a unique ability of IST to stimulate some naive HIV-specific T cell responses. IST-derived SL9-specific CD8+ T cells exhibited potent cytotoxicity, diverse TCR clonotypes, and memory-differentiated phenotypes, marking a significant advance in generating antigen-specific T cells against HIV. The modular IST platform provides a scalable modality to stimulate naive CD8+ T cells to potentially mobilize preemptive CD8+ T cell responses against predicted immune escape variants, as well as subdominant conserved HIV epitopes to empower the development of innovative ACT, vaccine, and other immune strategies to advance treatments for HIV, other persistent viral infections, and cancer. IMPORTANCE: Adoptive transfer of -expanded T cells with potent and broad anti-HIV activity may control HIV replication in people with HIV in the absence of antiretroviral therapy. To selectively activate and expand naive CD8+ cells targeting defined viral or cancer epitopes, we developed a unique protein architecture, termed Immuno-STAT, which delivers cognate peptide-specific T cell receptor (TCR) activation alone or in combination with CD28 costimulation. We demonstrated that polyfunctional cytotoxic CD8+ T cells specific for the HIV-associated SL9 or melanoma-associated MART-1 epitopes were expanded by αCD28-Immuno-STAT delivering peptide-specific TCR and CD28 signals, but not peptide-specific TCR signals alone. αCD28-Immuno-STAT-generated SL9-specific CD8+ T cells exhibited diverse TCR clonotypes, polyfunctionality, and potent SL9-specific cytotoxicity. Adoptive transfer of αCD28-Immuno-STAT-generated CD8+ T cells specific for defined HIV epitopes may provide the broad yet targeted responses specific for conserved HIV epitopes and predicted immune escape variants required to control HIV replication and provide a functional HIV cure.
未标记：过继性细胞转移（ACT）是一种很有前景的免疫治疗方法，分别通过扩增和输注抗原特异性CD8⁺T细胞来治疗病毒感染或癌症。然而，其更广泛的应用受到与传统方法相关的后勤挑战的限制，传统方法是使用负载肽的患者来源的树突状细胞（DCs）来扩增抗原特异性CD8⁺T细胞。为了克服这些限制，我们开发了免疫信号转导激活子（IST），这是一种二聚体蛋白支架，可在有或没有CD28共刺激信号的情况下传递肽特异性T细胞受体（TCR）激活信号，以扩增针对特定病毒或癌症表位的CD8⁺T细胞。在这项概念验证研究中，我们证明抗CD28-IST可以选择性地激活和扩增来自初始库的多功能细胞毒性CD8⁺T细胞，靶向与HIV相关的SL9或与黑色素瘤相关的MART-1表位。负载肽的DCs和IST都能可靠地扩增初始MART-1特异性CD8⁺T细胞。相比之下，初始SL9特异性CD8⁺T细胞仅通过SL9特异性IST扩增，而不是通过基于传统DC的方法扩增这突出了IST刺激某些初始HIV特异性T细胞反应的独特能力。IST衍生的SL9特异性CD8⁺T细胞表现出强大的细胞毒性、多样的TCR克隆型和记忆分化表型，标志着在产生针对HIV的抗原特异性T细胞方面取得了重大进展。模块化的IST平台提供了一种可扩展的方式来刺激初始CD8⁺T细胞，以潜在地动员针对预测的免疫逃逸变体的先发制人的CD8⁺T细胞反应，以及亚优势保守HIV表位，以推动创新的ACT、疫苗和其他免疫策略的发展，从而推进对HIV、其他持续性病毒感染和癌症的治疗。 重要性：过继性转移具有强大且广泛抗HIV活性的扩增T细胞可能在无抗逆转录病毒治疗的情况下控制HIV感染者体内的HIV复制。为了选择性地激活和扩增靶向特定病毒或癌症表位的初始CD8⁺细胞，我们开发了一种独特的蛋白质结构，称为免疫信号转导激活子（Immuno-STAT），它可单独或与CD28共刺激一起传递同源肽特异性T细胞受体（TCR）激活信号。我们证明，通过αCD28-免疫信号转导激活子传递肽特异性TCR和CD28信号可扩增针对与HIV相关的SL9或与黑色素瘤相关的MART-1表位的多功能细胞毒性CD8⁺T细胞，但单独的肽特异性TCR信号则不行。αCD28-免疫信号转导激活子产生的SL9特异性CD8⁺T细胞表现出多样的TCR克隆型、多功能性和强大的SL9特异性细胞毒性。过继性转移αCD28-免疫信号转导激活子产生的针对特定HIV表位的CD8⁺T细胞可能提供针对保守HIV表位和预测的免疫逃逸变体的广泛而有针对性的反应，这是控制HIV复制和实现功能性HIV治愈所需的。
Cochrane Database Syst Rev. 2018-2-6
Transplant Cell Ther. 2024-1
Zotero 插件