Chaperoning epitopes to induce protective T cell responses

项目摘要 CD 8 T细胞介导的免疫有助于清除许多病毒和保护免受 继发感染。随着癌症疫苗的出现和对细胞在癌症中的核心作用的更好理解， T细胞应答是现代疫苗学的前沿。合成长肽（SLP） 疫苗接种在宫颈癌试验中被证明是有效的，我们已经证明SLP可以用来集中T细胞， 感染性疾病的细胞反应。尽管SLP具有优势和临床前疗效， 有时使用有毒和昂贵的实验佐剂来诱导免疫应答。而且 SLP的免疫原性受到可溶性肽向树突细胞（DC）相对较差的递送的阻碍 以及泛素-蛋白酶体系统（UPS）将SLP加工成短肽的次优加工， 然后呈递给CD 8 T细胞。在这里，我们建议测试由纳米颗粒组成的基于SLP的疫苗 装载有表位特异性SLP，该表位特异性SLP用募集E3泛素的蛋白水解靶向分子（ProTM）修饰 连接酶，从而优化通过UPS的SLP降解和随后将SLP表位呈递给T细胞。 我们计划合成、优化和测试一种SLP疫苗，该疫苗利用可生物降解的纳米颗粒， T细胞活化佐剂或用内体逃逸结构域（EED）和ProTM修饰的SLP。我们 预期我们的疫苗将通过靶向佐剂和修饰的SLP来引发强有力的T细胞应答， 区议会一旦内化，SLP将从可生物降解的颗粒中释放，进入胞质溶胶， 被运输到UPS进行降解，从而增强通过MHCI向CD 8 T细胞的肽呈递。我们 一项提案描述了一种疫苗平台，可以很容易地定制来治疗恶性肿瘤或预防性地 产生针对传染病的保护性T细胞应答。这是第一个疫苗平台， ProTM增强抗原呈递给T细胞。

Project Summary CD8 T cell mediated immunity is instrumental in the clearance of numerous viruses and protection from secondary infections. With the advent of cancer vaccines and a better appreciation for the central role of cell mediated immunity, T cell responses are at the forefront of modern vaccinology. Synthetic Long Peptide (SLP) vaccination has proved effective in cervical cancer trials and we have shown that SLPs can be used to focus T cell responses in infectious disease. Despite their advantages and preclinical efficacy, SLPs must be formulated with sometimes toxic and expensive experimental adjuvants to induce immune responses. Furthermore, the immunogenicity of SLPs is hampered by the relatively poor delivery of soluble peptides to dendritic cells (DCs) and the suboptimal processing of SLPs by the ubiquitin-proteasome system (UPS) into short peptides that are then presented to CD8 T cells. Here, we propose to test an SLP-based vaccine composed of nanoparticles loaded with epitope specific SLPs modified with a proteolysis targeting molecule (ProTM) that recruits E3 ubiquitin ligase, thus optimizing SLP degradation via the UPS and subsequent presentation of SLP epitopes to T cells. We plan to synthesize, optimize, and test an SLP vaccine that utilizes biodegradable nanoparticles loaded with either a T cell-activating adjuvant or SLPs modified with an endosomal escaped domain (EED) and ProTM. We anticipate that our vaccine will elicit robust T cell responses by targeting both adjuvants and modified SLPs to DCs. Once internalized, SLP's will be released from the biodegradable particles, gain access to the cytosol, and be trafficked to the UPS for degradation, thus enhancing peptide presentation via MHCI to CD8 T cells. Our proposal describes a vaccine platform that can be easily tailored to treat malignancies or prophylactically to generate protective T cell responses against infectious disease. It is the first vaccine platform that utilizes ProTMs to enhance antigen presentation to T cells.