Department of Pathology, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II 307, Baltimore, MD, 21287, USA.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Biomed Sci. 2024 Jan 29;31(1):19. doi: 10.1186/s12929-024-01006-9.
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.
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 CD44 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 CD44 CD8 T cells.
CD44 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 CD44 naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44 naïve CD8 T cells revealed FLT3L to induce CD44 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 CD44 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 CD44 CD8 T cells.
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.
先前关于 FMS 样酪氨酸激酶 3 配体（FLT3L）的研究主要集中在其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 在体内对 CD8 T 细胞免疫调节能力的作用。
生成白蛋白结合的 FLT3L（Alb-FLT3L）并将其用于转化医学目的；在这里，它被用于治疗 naive C57BL/6 和 OT1 小鼠，以分析 CD8 T 细胞反应。使用同源 B16ova 和 E.G7ova 小鼠模型进行过继细胞转移，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 调节的潜在机制，我们对 CD44 CD8 T 细胞进行了批量 RNA-seq 分析。使用 STAT1 缺陷型小鼠阐明 Alb-FLT3L 在调节 T 细胞中的功能作用。最后，通过阻断 I 型干扰素信号和体外共培养浆细胞样树突状细胞（pDC）与幼稚 CD8 T 细胞来确定 pDC 在介导 CD44 CD8 T 细胞调节中的作用。
Alb-FLT3L 处理的 C57BL/6 小鼠中 CD44 CD8 T 细胞增强。这些 CD8 T 细胞表现出虚拟记忆特征，具有更强的增殖和有效功能。值得注意的是，将 CD44 幼稚 CD8 T 细胞过继转移到具有 B16ova 肿瘤的 C57BL/6 小鼠中，导致肿瘤明显消退。CD44 幼稚 CD8 T 细胞的 RNA-seq 分析表明，FLT3L 通过 JAK-STAT1 信号通路诱导 CD44 CD8 T 细胞，这一结果得到了支持，表明与野生型对照小鼠相比，STAT1 缺陷型小鼠中 FLT3L 增强 CD8 T 细胞增殖的能力降低。此外，阻断 I 型干扰素信号限制了 FLT3L 诱导的 CD44 CD8 T 细胞的产生，而在与来自 Alb-FLT3L 处理小鼠的 pDC 共培养的幼稚 CD8 T 细胞中能够诱导 CD44 表达。这表明 pDC 在介导 FLT3L 对 CD44 CD8 T 细胞的调节中起着关键作用。
这些发现提供了关键的见解，并支持 Alb-FLT3L 作为一种免疫调节剂在癌症免疫治疗中对幼稚 CD8 T 细胞进行预处理的治疗潜力。
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