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Complex Consisting of β-Glucan and Antigenic Peptides with Cleavage Site for Glutathione and Aminopeptidases Induces Potent Cytotoxic T Lymphocytes
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-08-09 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00159 Shinichi Mochizuki 1 , Hiromi Morishita 1 , Kazuo Sakurai 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-08-09 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00159 Shinichi Mochizuki 1 , Hiromi Morishita 1 , Kazuo Sakurai 1
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The efficient induction of antigen-specific immune responses requires not only promotion of the uptake of antigens and adjuvant molecules into antigen-presenting cells but also control of their intracellular behavior. We previously demonstrated that the β-glucan schizophyllan (SPG) can form complexes with CpG oligonucleotides with attached dA40 (CpG-dA/SPG), which can accumulate in macrophages in the draining inguinal lymph nodes and induce strong immune responses. In this study, we prepared various conjugates composed of antigenic peptide (OVA257–264) and dA40 and made complexes with SPG. The conjugates with a disulfide bond between OVA257–264 and dA40 were easily cleaved by glutathione. The resultant peptides with a hydrophobic amino acid at the C-terminal end was recognized by puromycin-insensitive leucine aminopeptidase (PILS-AP), which trims antigenic peptide precursors and prepares peptides of eight or nine amino acids in length, which is the optimal length for binding to major histocompatibility complex (MHC)-I. The conjugate exposed to such enzymes induced a high antigen presentation level. The antigen presentation level was almost the same before and after the complexation with SPG. Immunization with a mixture of dA–OVA257–264/SPG and CpG–dA/SPG induced high antigen-specific cytotoxic T-lymphocyte activity at a much lower peptide dose than in previous studies. These results can be strongly ascribed to not only the cell-specific delivery by SPG but also the control of the intracellular behavior by the introduction of cleavage sites. Therefore, peptide–dA/SPG complexes could be used as potent vaccine antigens for the treatment of cancers and infectious diseases.
中文翻译：
β-葡聚糖和抗原肽与谷胱甘肽和氨基肽酶切割位点的复合物诱导有效的细胞毒性T淋巴细胞。
有效诱导抗原特异性免疫反应不仅需要促进抗原和佐剂分子对抗原呈递细胞的摄取，而且需要控制其细胞内行为。我们先前证明，β-葡聚糖裂褶多糖（SPG）可以与带有dA 40（CpG-dA / SPG）的CpG寡核苷酸形成复合物，后者可以积聚在引流性腹股沟淋巴结中的巨噬细胞中，并诱导强烈的免疫反应。在这项研究中，我们制备了由抗原肽（OVA 257–264）和dA 40组成的各种结合物，并与SPG形成了复合物。OVA 257–264与dA 40之间具有二硫键的共轭物容易被谷胱甘肽裂解。嘌呤霉素不敏感的亮氨酸氨基肽酶（PILS-AP）识别出C端具有疏水性氨基酸的肽，该酶修整抗原肽前体并制备长度为八或九个氨基酸的肽，这是最佳长度用于与主要组织相容性复合物（MHC）-I结合。暴露于此类酶的结合物诱导了高抗原呈递水平。与SPG络合之前和之后，抗原呈递水平几乎相同。混合使用dA–OVA 257–264进行免疫/ SPG和CpG–dA / SPG以比以前的研究低得多的肽剂量诱导了高抗原特异性细胞毒性T淋巴细胞活性。这些结果不仅可以归因于通过SPG进行的细胞特异性递送，而且还可以归因于通过引入切割位点来控制细胞内行为。因此，肽-dA / SPG复合物可用作治疗癌症和传染病的有效疫苗抗原。
更新日期：2017-08-09
中文翻译：
β-葡聚糖和抗原肽与谷胱甘肽和氨基肽酶切割位点的复合物诱导有效的细胞毒性T淋巴细胞。
有效诱导抗原特异性免疫反应不仅需要促进抗原和佐剂分子对抗原呈递细胞的摄取，而且需要控制其细胞内行为。我们先前证明，β-葡聚糖裂褶多糖（SPG）可以与带有dA 40（CpG-dA / SPG）的CpG寡核苷酸形成复合物，后者可以积聚在引流性腹股沟淋巴结中的巨噬细胞中，并诱导强烈的免疫反应。在这项研究中，我们制备了由抗原肽（OVA 257–264）和dA 40组成的各种结合物，并与SPG形成了复合物。OVA 257–264与dA 40之间具有二硫键的共轭物容易被谷胱甘肽裂解。嘌呤霉素不敏感的亮氨酸氨基肽酶（PILS-AP）识别出C端具有疏水性氨基酸的肽，该酶修整抗原肽前体并制备长度为八或九个氨基酸的肽，这是最佳长度用于与主要组织相容性复合物（MHC）-I结合。暴露于此类酶的结合物诱导了高抗原呈递水平。与SPG络合之前和之后，抗原呈递水平几乎相同。混合使用dA–OVA 257–264进行免疫/ SPG和CpG–dA / SPG以比以前的研究低得多的肽剂量诱导了高抗原特异性细胞毒性T淋巴细胞活性。这些结果不仅可以归因于通过SPG进行的细胞特异性递送，而且还可以归因于通过引入切割位点来控制细胞内行为。因此，肽-dA / SPG复合物可用作治疗癌症和传染病的有效疫苗抗原。
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