mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.
mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.
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DOI：
10.3389/fimmu.2022.899975
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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调节性 T 细胞 (Treg) 作为多种同种免疫和自身免疫疾病的细胞治疗手段显示出了巨大的前景——部分原因在于它们的免疫抑制效力。然而，人类Tregs在患者中的临床疗效因其较差的体内稳态而受到限制。为了避免细胞凋亡，Treg 需要稳定的抗原（CD3δ/T 细胞受体介导）、共刺激（CD28 驱动）和细胞因子（IL-2 依赖性）信号传导。值得注意的是，该信号序列支持激活的 Treg 表型，其中包括颗粒酶，特别是颗粒酶 B (GrB) 的高表达。此前，我们已经证明，除了 GrB 在裂解靶细胞以调节同种免疫方面的功能作用外，GrB 还可以从宿主 Tregs 的细胞内溶酶体颗粒中漏出，启动促凋亡途径。在这里，我们评估了抑制雷帕霉素复合物 1 (mTORC1)（移植领域最近青睐的药物靶点）的机制靶点在通过 GrB 调节人 Treg 细胞凋亡中的作用。使用人类Treg培养的离体模型和人类皮肤同种异体移植的人源化小鼠模型，我们发现通过使用雷帕霉素抑制mTORC1，宿主Treg中GrB的胞质内表达和功能减弱；通过部分降低 S6K 和 c-Jun 的磷酸化来降低人 Treg 细胞凋亡。这些发现支持了 mTORC1 抑制在患者中已经经过临床验证的效果，最显着的是它们对 Treg 生物活性和体内稳态的稳定作用。
Regulatory T cells (Tregs) have shown great promise as a means of cellular therapy in a multitude of allo- and auto-immune diseases—due in part to their immunosuppressive potency. Nevertheless, the clinical efficacy of human Tregs in patients has been limited by their poor in vivo homeostasis. To avert apoptosis, Tregs require stable antigenic (CD3ζ/T-cell-receptor-mediated), co-stimulatory (CD28-driven), and cytokine (IL-2-dependent) signaling. Notably, this sequence of signals supports an activated Treg phenotype that includes a high expression of granzymes, particularly granzyme B (GrB). Previously, we have shown that aside from the functional effects of GrB in lysing target cells to modulate allo-immunity, GrB can leak out of the intracellular lysosomal granules of host Tregs, initiating pro-apoptotic pathways. Here, we assessed the role of inhibiting mechanistic target of rapamycin complex 1 (mTORC1), a recently favored drug target in the transplant field, in regulating human Treg apoptosis via GrB. Using ex vivo models of human Treg culture and a humanized mouse model of human skin allotransplantation, we found that by inhibiting mTORC1 using rapamycin, intracytoplasmic expression and functionality of GrB diminished in host Tregs; lowering human Treg apoptosis by in part decreasing the phosphorylation of S6K and c-Jun. These findings support the already clinically validated effects of mTORC1 inhibition in patients, most notably their stabilization of Treg bioactivity and in vivo homeostasis.