AIDS Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Mol Ther. 2013 Jul;21(7):1445-55. doi: 10.1038/mt.2013.63. Epub 2013 Apr 16.
Understanding and identifying new ways of mounting an effective CD8⁺ T cell immune response is important for eliminating infectious pathogens. Although upregulated programmed death-1 (PD1) in chronic infections (such as HIV-1 and tuberculosis) impedes T cell responses, blocking this PD1/PD-L pathway could functionally rescue the "exhausted" T cells. However, there exists a number of PD1 spliced variants with unknown biological function. Here, we identified a new isoform of human PD1 (Δ42PD1) that contains a 42-nucleotide in-frame deletion located at exon 2 domain found expressed in peripheral blood mononuclear cells (PBMCs). Δ42PD1 appears to function distinctly from PD1, as it does not engage PD-L1/PD-L2 but its recombinant form could induce proinflammatory cytokines. We utilized Δ42PD1 as an intramolecular adjuvant to develop a fusion DNA vaccine with HIV-1 Gag p24 antigen to immunize mice, which elicited a significantly enhanced level of anti-p24 IgG1/IgG2a antibody titers, and important p24-specific and tetramer⁺CD8⁺ T cells responses that lasted for ≥7.5 months. Furthermore, p24-specific CD8⁺ T cells remain functionally improved in proliferative and cytolytic capacities. Importantly, the enhanced antigen-specific immunity protected mice against pathogenic viral challenge and tumor growth. Thus, this newly identified PD1 variant (Δ42PD1) amplifies the generation of antigen-specific CD8⁺ T cell immunity when used in a DNA vaccine.
理解和识别新的方法来有效地产生 CD8+T 细胞免疫反应对于消除传染性病原体很重要。虽然慢性感染（如 HIV-1 和结核病）中程序性死亡受体 1（PD1）的上调会阻碍 T 细胞反应，但阻断这种 PD1/PD-L 途径可以在功能上拯救“衰竭”的 T 细胞。然而，存在许多具有未知生物学功能的 PD1 剪接变体。在这里，我们鉴定了一种新型的人类 PD1 异构体（Δ42PD1），它在位于外显子 2 结构域的 42 个核苷酸内缺失，在周围血单核细胞（PBMC）中表达。Δ42PD1 似乎与 PD1 有明显不同的功能，因为它不与 PD-L1/PD-L2 结合，但它的重组形式可以诱导促炎细胞因子。我们利用 Δ42PD1 作为分子内佐剂，用 HIV-1 Gag p24 抗原开发融合 DNA 疫苗来免疫小鼠，这引发了显著增强的抗 p24 IgG1/IgG2a 抗体滴度，以及重要的 p24 特异性和四聚体+CD8+T 细胞反应，持续时间≥7.5 个月。此外，p24 特异性 CD8+T 细胞的增殖和细胞毒性能力仍保持功能改善。重要的是，增强的抗原特异性免疫保护小鼠免受致病性病毒攻击和肿瘤生长。因此，当用于 DNA 疫苗时，这种新鉴定的 PD1 变体（Δ42PD1）可增强抗原特异性 CD8+T 细胞免疫的产生。
