Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4032-E4040. doi: 10.1073/pnas.1718434115. Epub 2018 Apr 9.
A technology to prime desired populations of T cells in the body-particularly those that possess low avidity against target antigen-would pave the way for the design of new types of vaccination for intractable infectious diseases or cancer. Here, we report such a technology based on positive feedback-driven, programmed self-assembly of peptide-major histocompatibility complex (pMHC) directly on the membrane of cognate T cells. Our design capitalizes on the unique features of the protein annexin V (ANXA5), which-in a concerted and synergistic manner-couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC-TCR affinity, with repeated pMHC encounters, and with widespread TCR cross-linking. In our system, ANXA5 is linked to pMHC and firmly engages the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. ANXA5, in turn, exerts a mechanical force that stabilizes interactions at the TCR-pMHC interface and facilitates repeated, serial pMHC encounters. Furthermore, ANXA5 quickly arranges into uniform 2D matrices, thereby prompting TCR cross-linking. Fusion of ANXA5 to pMHC augments lymphocyte activation by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to the application of synthetic, feedback-driven self-assembly platforms in immune modulation.
一种能够在体内预先激活特定 T 细胞群体的技术——特别是那些对靶抗原亲和力较低的 T 细胞——将为设计针对难治性传染病或癌症的新型疫苗铺平道路。在这里，我们报告了一种基于正反馈驱动的、肽-主要组织相容性复合物（pMHC）在同源 T 细胞膜上程序化自组装的技术。我们的设计利用了蛋白 annexin V（ANXA5）的独特特性，它以协同和协同的方式将 TCR 信号的早期起始与 pMHC-TCR 亲和力的激增、与 pMHC 的反复接触以及 TCR 的广泛交联联系起来。在我们的系统中，ANXA5 与 pMHC 相连，并在 TCR 信号的早期起始时（且仅在此时）牢固地与同源 T 细胞的质膜结合。反过来，ANXA5 施加机械力，稳定 TCR-pMHC 界面的相互作用，并促进 pMHC 的反复、连续接触。此外，ANXA5 迅速排列成均匀的 2D 基质，从而促使 TCR 交联。ANXA5 与 pMHC 的融合使淋巴细胞的激活增强了几个数量级（>1000 倍），绕过了对共刺激的需求，并在体内打破了对模型自身抗原的耐受。我们的研究为应用合成的、反馈驱动的自组装平台进行免疫调节开辟了道路。
