Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA.
Cell Rep. 2024 Aug 27;43(8):114506. doi: 10.1016/j.celrep.2024.114506. Epub 2024 Jul 24.
Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C pDCs, which, compared to Ly6C pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.
树突状细胞（DCs）的功能和表型异质性在促进宿主保护所必需的多样化免疫反应的发展中起着至关重要的作用。在这里，我们报告组蛋白赖氨酸去甲基酶 KDM5C 调节常规或经典 DC（cDC）和浆细胞样 DC（pDC）群体异质性和功能。在 DC 中缺乏 KDM5C 的小鼠中，cDC2Bs 和 cDC1s 的比例增加，这部分依赖于 I 型干扰素（IFN）和 pDCs。KDM5C 的缺失导致 Ly6C pDC 增加，与 Ly6C pDC 相比，Ly6C pDC 产生 I 型 IFN 的能力有限，更有效地刺激抗原特异性 CD8 T 细胞。KDM5C 缺陷型 DC 中炎症基因的表达增加，谱系特异性基因的表达改变，功能降低。在李斯特菌感染中，由于 cDC1 抗原呈递减少，KDM5C 缺陷型小鼠的 CD8 T 细胞反应减少。因此，KDM5C 是 DC 异质性的关键调节剂，也是 DC 功能特性的关键驱动因素。
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