Exploring and exploiting metabolic plasticity in regulatory T cells

项目摘要 调节性T(Treg)细胞代表免疫反应中的关键细胞角色，任务是维持 在豁免权方面的平衡。Treg细胞具有强大的抑制功能，维持免疫动态平衡， 防止自身免疫，并抑制强大的免疫反应，以防止侧枝组织损伤。这些细胞 是至关重要的，它们的不足或丧失会导致自身免疫。然而，它们也可能会结束- 激活，防止对慢性病毒感染和癌症的有效免疫。我们和其他人假设 Treg细胞与传统T细胞的不同之处不仅在于它们的功能，还在于它们如何为这种功能提供燃料。这个 新陈代谢和免疫的交叉最近引起了极大的兴趣；我们的实验室研究了 能量学影响免疫细胞功能，重点是肿瘤微环境中的免疫。我们 假设，由于调节性T细胞与它们的常规T细胞不同步，抑制 自身免疫或抑制组织中的生产性免疫，它们表现出代谢可塑性，能够持续 并在环境中的替代代谢底物上茁壮成长。我们的初步研究支持这一点。 假设，以癌症为模型。肿瘤浸润性Treg细胞异常活跃和增殖， 并在受到大量炎症性侮辱的情况下保持表观遗传和血统的稳定性，因此代表着一种 一个典型的调节细胞模型。我们发现Treg细胞“分层”成不同的代谢亚群 具有不同的抑制能力。这个新的创新者项目试图理解 在癌症和其他疾病中，微环境通过代谢共生促进Treg细胞的功能。 我们提出了利用肿瘤细胞代谢副产物的替代代谢途径的证据，这可能 支持Treg细胞在组织中的功能。我们将根据这些细胞的转录图谱来探索， 肿瘤微环境中存在的代谢物支持Treg细胞的功能和表观遗传稳定性。此外， 我们已经开发了一种新的系统，通过它可以在Treg细胞特异性的 举止。总而言之，这些研究将阐明这些关键细胞是如何被癌症利用的 逃避免疫反应，但也开辟了这些细胞可能用于治疗的潜在途径 通过代谢手段进行调节，以防止自身免疫或促进癌症的抗肿瘤反应。

PROJECT ABSTRACT Regulatory T (Treg) cells represent key cellular players in the immune response, tasked with maintaining balance in immunity. Endowed with potent suppressive function, Treg cells maintain immune homeostasis, prevent autoimmunity, and curtail robust immune responses to prevent collateral tissue damage. These cells are critically important, and their insufficiency or loss results in autoimmunity. However, they can also be over- activated, preventing effective immunity to chronic viral infections and cancer. We and others hypothesize that Treg cells differ from conventional T cells not only in their function, but also in how they fuel that function. The intersection of metabolism and immunity has been of immense recent interest; our laboratory studies how energetics impacts immune cell function with a focus on immunity in the tumor microenvironment. We hypothesize that, as regulatory T cells exist out-of-sync with their conventional counterparts, suppressing autoimmunity or curtailing productive immunity in the tissues, they exhibit metabolic plasticity, able to persist and thrive on alternative metabolic substrates in the environment. Our preliminary studies support this hypothesis, using cancer as a model. Tumor-infiltrating Treg cells are extraordinarily active and proliferative, and maintain their epigenetic and lineage stability despite substantial inflammatory insults and thus represent a model of an exemplary regulatory cell. We have found that Treg cells `stratify' into distinct metabolic subsets with different suppressive capacities. This New Innovator project seeks to understand how the microenvironment, in cancer and in other diseases, promotes Treg cell function through metabolic symbiosis. We present evidence of alternative metabolic pathways utilizing byproducts of tumor cell metabolism that may support Treg cell function in the tissues. We will explore, based on transcriptomic profiles of these cells, which metabolites present in the tumor microenvironment support Treg cell function and epigenetic stability. Further, we have developed a novel system by which certain metabolic pathways can be enforced in a Treg cell-specific manner. Taken together, these studies will shed light on how these crucial cells are exploited by cancer to evade the immune response but also open up potential avenues by which these cells may be therapeutically modulated through metabolic means to prevent autoimmunity or promote the anti-tumor response in cancer.