Inducing Tolerance with 5-Module chimeric Antigen Receptor (5MCAR) T Cells

项目总结 T细胞对MHC分子提呈的多肽抗原(PMHC)作出反应。它们是由5模块驱动的 大复合体，由一个受体模块[T细胞受体(TCR)]，三个信号模块组成 (cd3δε，cd3γε，cd3ζζ)，以及cd4或cd8共受体模块，允许T细胞对单个 激动剂pMHC与向细胞毒(CTL)、辅助性(Th)、调节性(Treg)或记忆(TM)细胞的直接分化 对生产性免疫至关重要的表型。重要的是，T细胞也有致病风险 自身或移植抗原特异性且不受外周耐受控制的应答 机械装置。因此，驱动T细胞活动的大分子复合体既来自工程学，也是有趣的 观点，因为它们是设计重定向T细胞的新型嵌合受体的理想框架 细胞疗法，从靶向的角度来看，旨在减轻T细胞介导的病理 当忍耐力崩溃时。这项提议将测试使用新的5模块嵌合抗原的有效性。 受体系统(5MCAR)，已被设计为根据机械原理运行， 管理TCR-CD3-pMHC-CD4/CD8大分子复合体，将CTL重定向至靶向致病T细胞。我们的 目标是：使用5MCAR-CTL消除pMHC特异性T细胞群，包括致病T细胞，通过 手术打击，以诱导小鼠模型的耐受；以及，设计并测试人源化的5MCARs在 人性化的老鼠模型系统。工作完成后，将为5MCAR-CTL的使用提供蓝图 诱导对已定义的pMHC的耐受和减轻T细胞介导的病理的治疗。

PROJECT SUMMARY T cells respond to peptide antigens presented by MHC molecules (pMHC). They are driven by 5-module macrocomplexes, composed of one receptor module [the T cell receptor (TCR)], three signaling modules (CD3δε, CD3γε, CD3ζζ), and a CD4 or CD8 coreceptor module, that allow T cells to respond to a single agonist pMHC and direct differentiation to cytotoxic (CTL), helper (Th), regulatory (Treg), or memory (Tm) cell phenotypes that are essential for productive immunity. Importantly, T cells also pose the risk of pathogenic responses if they are specific to self or transplant antigens and are not controlled by peripheral tolerance mechanisms. The macrocomplexes that drive T cell activity are therefore interesting both from an engineering standpoint, as they serve as an ideal framework upon which to design novel chimeric receptors for redirected T cell therapy, and from a targeting standpoint for therapies aimed at mitigating T cell-mediated pathologies when tolerance breaks down. This proposal will test the efficacy of using a novel 5-module chimeric antigen receptor system (5MCAR), which has been engineered to operate according to the mechanistic principles that govern the TCR-CD3-pMHC-CD4/CD8 macrocomplexes, to redirect CTLs to target pathogenic T cells. Our goals are to: use 5MCAR-CTLs to eliminate pMHC-specific T cell populations, including pathogenic T cells, via a surgical strike in order to induce tolerance in mouse models; and, engineer and test humanized 5MCARs in a humanized mouse model system. When completed, the work will provide a blueprint for using 5MCAR-CTL therapy to induce tolerance to defined pMHC and mitigate T cell-mediated pathologies.