Skeletal Muscle Is an Antigen Reservoir in Integrase-Defective Lentiviral Vector-Induced Long-Term Immunity.,Molecular Therapy - Methods & Clinical Development

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Skeletal Muscle Is an Antigen Reservoir in Integrase-Defective Lentiviral Vector-Induced Long-Term Immunity.
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.omtm.2020.03.008
Yi-Yu Lin _{1,

2} , Ian Belle ₁ , Maria Blasi _{1,

2} , Min-Nung Huang ₁ , Anne F Buckley ₃ , Wes Rountree ₂ , Mary E Klotman _{1,

2} , Andrea Cara _{1,

2,

4} , Donatella Negri _{1,

2,

5}

Affiliation

We previously developed integrase-defective lentiviral vectors (IDLVs) as an antigen delivery system for inducing strong and prolonged immunity in animal models. Here, we examined the association between persistence of antigen expression and durability of immune response. Following a single intramuscular (i.m.) or subcutaneous (s.c.) injection of IDLV delivering GFP in mice, we evaluated antigen expression and inflammation at the site of injection and persistence of antigen-specific T cells at early and late time points. Durable antigen expression was detected up to 90 days only after i.m. immunization. Mononuclear inflammation was evident soon after IDLV injection in both i.m. and s.c. immunized mice, but remained detectable up to 30 days postinjection only in i.m. immunized mice. Similarly, GFP-specific T cells were more persistent in the i.m. immunized mice. Interestingly, GFP+ muscle fibers were co-expressing major histocompatibility complex (MHC) class I, suggesting that muscle cells are competent for presenting antigens to T cells in vivo. In in vitro experiments, we demonstrated that although both primary myoblasts and myocytes present the antigen to GFP-specific T cells through MHC class I, myoblasts are more resistant to Fas-dependent cytotoxic T lymphocyte (CTL) killing activity. Overall, these data indicate that muscle cells may serve as an antigen reservoir that contributes to the long-term immunity induced by IDLV vaccination.

中文翻译：

骨骼肌是整合酶缺陷型慢病毒载体诱导的长期免疫中的抗原库。

我们之前开发了整合酶缺陷型慢病毒载体（IDLV）作为抗原递送系统，用于在动物模型中诱导强而持久的免疫力。在这里，我们检查了抗原表达的持久性与免疫反应的持久性之间的关联。在小鼠中单次肌内 (im) 或皮下 (sc) 注射 IDLV 递送 GFP 后，我们评估了注射部位的抗原表达和炎症，以及抗原特异性 T 细胞在早期和晚期时间点的持续性。仅在免疫接种后长达 90 天才检测到持久抗原表达。在肌内和皮下免疫小鼠中注射 IDLV 后不久，单核炎症就很明显，但仅在免疫小鼠中注射后长达 30 天仍可检测到。同样，GFP 特异性 T 细胞在免疫小鼠中更持久。有趣的是，GFP+ 肌纤维共表达 I 类主要组织相容性复合体 (MHC)，表明肌细胞能够在体内向 T 细胞呈递抗原。在体外实验中，我们证明，尽管原代成肌细胞和肌细胞都通过 MHC I 类向 GFP 特异性 T 细胞呈递抗原，但成肌细胞对 Fas 依赖性细胞毒性 T 淋巴细胞 (CTL) 杀伤活性更具抵抗力。总体而言，这些数据表明肌肉细胞可能作为抗原库，有助于 IDLV 疫苗接种诱导的长期免疫力。

更新日期：2020-03-13

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