Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA.
Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD, 21201, USA.
Sci Rep. 2022 Jul 19;12(1):12311. doi: 10.1038/s41598-022-16548-x.
Dendritic cells (DCs) play pivotal roles in initiating and shaping both innate and adaptive immune responses. The spatiotemporal expression of transcription factor networks and activation of specific signal transduction pathways determine the specification, distribution and differentiation of DC subsets. Even though pioneering studies have established indispensable roles for specific catalytic subunits (p110δ and p110γ) in immune cells, functions of the regulatory subunits, particularly of Class I PI3K, within the hematopoietic system remain incompletely understood. In the study presented here, we deleted the key regulatory subunits-p85α and p85β of the Class I PI3K in hematopoietic cells and studied its impact on DC differentiation. Our studies identify that a deficiency of p85 causes increased differentiation of conventional DC (cDC) 2 and plasmacytoid DC (pDC) subsets in the spleen. On the other hand, DC numbers in the bone marrow (BM), thymus and lymph nodes were decreased in p85 mutant mice. Analysis of DC-specific progenitors and precursors indicated increased numbers in the BM and spleen of p85 deficient mice. In-vitro differentiation studies demonstrated augmented DC-differentiation capacities of p85 deficient BM cells in the presence of GM-CSF and Flt3L. BM chimera studies established that p85 deficiency affects DC development through cell intrinsic mechanisms. Molecular studies revealed increased proliferation of DCs and common DC progenitors (CDPs) in the absence of p85 and altered signal transduction pathways in p85 mutant DC subsets in response to Flt3L. In essence, data presented here, for the first time, unequivocally establish that the P85α subunit of class I PI3Ks has an indispensable role in the development and maintenance of DCs.
树突状细胞 (DCs) 在启动和塑造先天免疫和适应性免疫反应方面发挥着关键作用。转录因子网络的时空表达和特定信号转导途径的激活决定了 DC 亚群的特异性、分布和分化。尽管开创性的研究已经确立了特定催化亚基（p110δ 和 p110γ）在免疫细胞中的不可或缺作用，但在造血系统中，调节亚基（特别是 I 类 PI3K）的功能仍不完全清楚。在本研究中，我们在造血细胞中删除了 I 类 PI3K 的关键调节亚基-p85α 和 p85β，并研究了其对 DC 分化的影响。我们的研究表明，p85 的缺失导致脾脏中常规 DC (cDC) 2 和浆细胞样 DC (pDC) 亚群的分化增加。另一方面，p85 突变小鼠骨髓 (BM)、胸腺和淋巴结中的 DC 数量减少。对 DC 特异性祖细胞和前体细胞的分析表明，p85 缺陷小鼠 BM 和脾脏中的数量增加。体外分化研究表明，p85 缺陷 BM 细胞在 GM-CSF 和 Flt3L 的存在下具有增强的 DC 分化能力。BM 嵌合体研究表明，p85 缺乏通过细胞内在机制影响 DC 发育。分子研究表明，在没有 p85 的情况下，DC 和共同 DC 祖细胞 (CDP) 的增殖增加，并且 p85 突变 DC 亚群对 Flt3L 的信号转导途径发生改变。从本质上讲，这里呈现的数据首次明确确立了 I 类 PI3Ks 的 P85α 亚基在 DC 的发育和维持中具有不可或缺的作用。
