MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells
MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells
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DOI：
10.4049/jimmunol.1100658
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发表时间：
2011-07-01
影响因子：
4.4
通讯作者：
Knutson, Keith L.
中科院分区：
文献类型：
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作者：
Erskine, Courtney L.;Krco, Christopher J.;Knutson, Keith L.
CD4 Th 细胞对于针对感染和肿瘤的协调免疫反应的发展至关重要。 Th 细胞通过 TCR 与与肽复合的 MHC II 类相互作用而被激活。 T 细胞活化取决于 MHC 肽复合物的密度以及 TCR 与 APC 相互作用的持续时间。在本研究中，我们试图确定 MHC II 类肽是否可以用促进摄取和呈递的氨基酸序列进行修饰，以改善体外和体内 Th 细胞的活化。源自小鼠叶酸受体 a（一种自身和肿瘤 Ag）的模型表位在其羧基末端用恒定链衍生的 Ii-Key 肽进行修饰，在其 N 末端用增强 APC 对 Ag 摄取的肽进行修饰。肽的修饰导致高亲和力鼠叶酸受体 T 细胞的产生增强，这些细胞在体内持续存在并定位于 Ag 沉积位点。嵌套方法与表位和物种无关，并且明确排除了 CD4 调节性 T 细胞的扩增。由此产生的 Th 细胞具有治疗作用，增强体内辅助活性，并增强抵抗耐受性免疫微环境的能力。除了改进的免疫佐剂之外，这种表位修饰策略还可用于增强 Th 细胞的离体和体内生成，从而预防和治疗疾病。免疫学杂志，2011，187：316-324。
CD4 Th cells are critical to the development of coordinated immune responses to infections and tumors. Th cells are activated through interactions of the TCR with MHC class II complexed with peptide. T cell activation is dependent on the density of MHC peptide complexes as well as the duration of interaction of the TCR with APCs. In this study, we sought to determine whether MHC class II peptides could be modified with amino acid sequences that facilitated uptake and presentation with the goal of improving Th cell activation in vitro and in vivo. A model epitope derived from the murine folate receptor a, a self-and tumor Ag, was modified at its carboxyl terminus with the invariant chain-derived Ii-Key peptide and at its N terminus with a peptide that enhances uptake of Ag by APC. Modification of a peptide resulted in enhanced generation of high-avidity murine folate receptor a T cells that persisted in vivo and homed to sites of Ag deposition. The nesting approach was epitope and species independent and specifically excluded expansion of CD4 regulatory T cells. The resulting Th cells were therapeutic, enhanced in vivo helper activity and had an increased ability to resist tolerizing immune microenvironments. In addition to improved immunoadjuvants, this epitope modification strategy may be useful for enhancing ex vivo and in vivo generation of Th cells for preventing and treating diseases. The Journal of Immunology, 2011, 187: 316-324.