FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors.

IF 9 2区 医学 Q1 CELL BIOLOGY
Hsin-Fang Tu, Yu-Jui Kung, Ling Lim, Julia Tao, Ming-Hung Hu, Michelle Cheng, Deyin Xing, T C Wu, Chien-Fu Hung
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引用次数: 0

Abstract

Background: Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells.

Methods: Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells.

Results: CD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells.

Conclusions: These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

FLT3L 诱导的虚拟记忆 CD8 T 细胞参与免疫系统对抗肿瘤。
背景:以往对FMS样酪氨酸激酶3配体(FLT3L)的研究主要集中在它们从骨髓祖细胞生成树突状细胞(DC)的潜力上,而对这些细胞如何影响CD8 T细胞功能的了解有限。在这项研究中,我们进一步研究了FLT3L对CD8 T细胞免疫调节能力的体内作用:方法:白蛋白结合的FLT3L(Alb-FLT3L)被生成并应用于转化医学目的;在此,它被用于治疗幼稚的C57BL/6和OT1小鼠,以进行CD8 T细胞反应分析。我们还利用接种B16ova和E.G7ova小鼠模型进行了采纳性细胞转移,以评估Alb-FLT3L预处理CD8 T细胞对肿瘤进展的影响。为了揭示 Alb-FLT3L 调节的内在机制,我们对 CD44high CD8 T 细胞进行了批量 RNA-seq 分析。我们利用 STAT1 缺陷小鼠来阐明 Alb-FLT3L 在调节 T 细胞中的功能作用。最后,通过抗体阻断一型干扰素信号传导以及质体DCs(pDCs)与幼稚CD8 T细胞体外共培养,确定了pDCs在介导调控CD44high CD8 T细胞中的作用:结果:使用 Alb-FLT3L 的 C57BL/6 小鼠的 CD44high CD8 T 细胞得到了增强。这些 CD8 T 细胞表现出虚拟记忆特征,并具有更强的增殖和有效功能。值得注意的是,将CD44高的天真CD8 T细胞收养性转移到患有B16ova肿瘤的C57BL/6小鼠体内可使肿瘤显著消退。对CD44high天真CD8 T细胞的RNA-seq分析表明,FLT3L以依赖JAK-STAT1信号通路的方式诱导CD44high CD8 T细胞。此外,抗体阻断一型干扰素信号传导限制了 FLT3L 诱导的 CD44 高 CD8 T 细胞的生成,而与来自 FLT3L 处理小鼠的 pDCs 共同培养的幼稚 CD8 T 细胞却能诱导 CD44 表达。这表明 pDCs 在介导 FLT3L 对 CD44 高的 CD8 T 细胞的调控中起着至关重要的作用:这些发现提供了重要的见解,支持了 Alb-FLT3L 作为免疫调节剂在癌症免疫疗法中预处理幼稚 CD8 T 细胞的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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