Heteroclitic and modified T cell epitopes in coronavirus encephalomyelitis

冠状病毒脑脊髓炎中的异斜和修饰 T 细胞表位

• 批准号: 8314410
• 负责人: Jonathan A Trujillo
• 金额: $ 2.89万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-18 至 2013-04-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314410
• 关键词: Acute; Affinity; Antibodies; Antigens; Attenuated; Avidity; Binding; Brain; CD8B1 gene; Cell Fraction; Cells; Chronic; Clinical; Collaborations; Complex; Coronavirus; Cytotoxic T-Lymphocytes; Demyelinating Diseases; Demyelinations; Discipline of Nursing; Disease; Encephalitis; Encephalomyelitis; Epitopes; Exhibits; Genome; Glycoproteins; Goals; Hindlimb; Histocompatibility Antigens Class I; Immune; Immune response; Immunization; Infection; Kinetics; Lymphocyte; MHC Class I Genes; Measurement; Mediating; Modeling; Modification; Molecular; Multiple Sclerosis; Murine hepatitis virus; Mus; Mutate; Mutation; Nurses; Paralysed; Peptide/MHC Complex; Peptides; Specificity; Spinal Cord; Structure; Surface; System; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Universities; Vaccine Design; Variant; Viral; Virus; analog; base; cytotoxic; design; human disease; immunogenicity; immunopathology; improved; mutant; neurotropic; pathogen; positional cloning; predictive modeling; prevent; pup; response; tumor; vaccine development; vaccine efficacy; virus-induced demyelination

DESCRIPTION (provided by applicant): Mice infected with the neurotropic JHM strain of the murine coronavirus, mouse hepatitis virus, (JHMV) develop acute and chronic demyelinating disease, which are useful models for the human disease, multiple sclerosis. In one version, suckling C57Bl/6 (B6) mice are infected with JHMV and are protected from developing acute encephalitis by nursing by JHMV-immune dams. A variable percentage of mice develop demyelinating encephalomyelitis 3-8 weeks after infection; this infection is characterized by mutations in the immunodominant CD8 T cell epitope (S510) recognized in B6 mice. These mutations abrogate recognition by S510-specific CD8 T cells (cytotoxic lymphocyte escape, CTL escape). A second epitope (S598) is also recognized in these mice, but the immune response to this epitope does not prevent CTL escape. However, modification of the S598 peptide that result in better binding to MHC class I antigen results in a CD8 T cell response with higher functional avidity. Remarkably, immunization with this modified epitope now selects for CD8 T cells that more potently recognize the native S598 epitope than do cells elicited by the original epitope, thereby exhibiting a heteroclitic effect. Immunization with the modified epitope protects against CTL escape. The main goal of this proposal is to probe why an epitope is heteroclitic. The first specific aim will evaluate the efficacy of the CD8 T cell response induced by the previously identified heteroclitic S598 epitope in diminishing demyelination after infection with an attenuated strain of JHMV. The second specific aim will identify other heteroclitic variants of S598 and to begin to identify features that facilitate prediction of such heteroclitic peptides; now heteroclitic epitopes are identified empirically. The third aim will perform structural and biophysical studies of S598-specific T cell receptors (TCRs) in complex with the native or heteroclitic S598 peptide bound to MHCI (H-2Kb). The ultimate goal is to understand the molecular basis of interactions between high affinity TCRs and heteroclitic epitope/MHC class I antigen. By understanding these interactions, it will be possible to design variant epitopes that induce CD8 T cells with high functional avidity that potently cross-react with the native epitope, but do not induce a large fraction of cells with unwanted specificity. This approach will be useful in design of vaccines that are directed at enhancing pathogen-specific CD8 T cell responses.

描述（由申请人提供）：感染鼠冠状病毒（小鼠肝炎病毒）的嗜神经性JHM株（JHMV）的小鼠发生急性和慢性脱髓鞘疾病，这是人类疾病多发性硬化症的有用模型。在一个版本中，用JHMV感染乳C57 B1/6（B6）小鼠，并通过JHMV免疫母鼠的护理来保护乳C57 B1/6（B6）小鼠免于发展急性脑炎。感染后3-8周，不同百分比的小鼠发生脱髓鞘性脑脊髓炎;这种感染的特征在于B6小鼠中识别的免疫显性CD 8 T细胞表位（S510）突变。这些突变消除了S510特异性CD 8 T细胞的识别（细胞毒性淋巴细胞逃逸，CTL逃逸）。第二个表位（S598）也在这些小鼠中被识别，但对该表位的免疫应答不阻止CTL逃逸。然而，导致与MHC I类抗原更好结合的S598肽的修饰导致具有更高功能亲合力的CD 8 T细胞应答。值得注意的是，用这种修饰的表位免疫现在选择比由原始表位引发的细胞更有效地识别天然S598表位的CD 8 T细胞，从而表现出不规则效应。用修饰的表位免疫保护免于CTL逃逸。该提议的主要目标是探索为什么表位是不规则的。第一个具体目标将评估由先前鉴定的异型S598表位诱导的CD 8 T细胞应答在用JHMV减毒株感染后减少脱髓鞘中的功效。第二个具体目标是鉴定S598的其他不规则变异体，并开始鉴定有助于预测这种不规则肽的特征;现在不规则表位是凭经验鉴定的。第三个目标将进行S598特异性T细胞受体（TCR）与天然或异型S598肽结合到MHCI（H-2Kb）的复合物的结构和生物物理研究。最终目标是了解高亲和力TCR与异型表位/MHC I类抗原之间相互作用的分子基础。通过理解这些相互作用，将有可能设计变体表位，其诱导具有高功能亲合力的CD 8 T细胞，其与天然表位有效地交叉反应，但不诱导大部分具有不需要的特异性的细胞。这种方法将有助于设计针对增强病原体特异性CD 8 T细胞应答的疫苗。