Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, Saarland University, Saarbrücken, Germany.
Eur J Immunol. 2023 Oct;53(10):e2250270. doi: 10.1002/eji.202250270. Epub 2023 Jun 27.
Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362 mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362 mice appeared clinically normal, showed no phenotypic alterations in the T-cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3 Treg cells and IL-10 and RORγt Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4 T cells from Zfp362 mice into Rag2 mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362 littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation.
黏膜屏障完整性和病原体清除是一个复杂的过程，受 Th17 和 Treg 细胞的影响。此前，我们已经描述了 Th17 细胞的 DNA 甲基化图谱，并确定锌指蛋白（Zfp）362 是唯一去甲基化的。在这里，我们生成了 Zfp362 敲除小鼠，以揭示 Zfp362 对 Th17 细胞生物学的作用。Zfp362 敲除小鼠在临床上看起来正常，T 细胞群中没有表型改变，在定植分段丝状菌后，Zfp362 缺乏对 Th17 细胞分化没有影响。相比之下，Zfp362 缺失导致结肠 Foxp3+Treg 细胞和肠系膜淋巴结中 IL-10 和 RORγt+Treg 细胞亚群的频率增加。将幼稚 CD4 T 细胞从 Zfp362 小鼠过继转移到 Rag2 小鼠中，与接受 Zfp362 同窝仔鼠细胞的对照相比，体重减轻明显减少。然而，这种减轻的体重减轻与 Th17 细胞的改变无关，而是与肠系膜淋巴结中效应性 Treg 细胞的增加相关。总之，这些结果表明 Zfp362 在促进结肠炎症中发挥重要作用；然而，这种功能源自对 Treg 细胞效应功能的限制，而不是直接促进 Th17 细胞分化。
