Class I PI3K regulatory subunits control differentiation of dendritic cell subsets and regulate Flt3L mediated signal transduction.
Class I PI3K regulatory subunits control differentiation of dendritic cell subsets and regulate Flt3L mediated signal transduction.
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DOI：
10.1038/s41598-022-16548-x
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发表时间：
2022-07-19
影响因子：
4.6
通讯作者：
Rathinam, Chozha Vendan
中科院分区：
文献类型：
--
作者：
Thummar, Keyur;Rathinam, Chozha Vendan
树突状细胞（dc）在启动和塑造先天和适应性免疫反应中起着关键作用。转录因子网络的时空表达和特定信号转导通路的激活决定了DC亚群的规格、分布和分化。尽管开创性的研究已经确立了免疫细胞中特定催化亚基（p110δ和p110γ）不可或缺的作用，但造血系统中调节亚基，特别是I类PI3K的功能仍然不完全清楚。在本研究中，我们删除了造血细胞中IA类PI3K的关键调控亚基p85α和p85β，并研究了其对DC分化的影响。我们的研究发现，p85的缺乏导致脾脏中常规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缺陷小鼠的BM和脾脏中dc特异性祖细胞和前体细胞数量增加。体外分化研究表明，在GM-CSF和Flt3L的存在下，p85缺陷BM细胞的dc分化能力增强。BM嵌合体研究证实p85缺陷通过细胞内在机制影响DC发育。分子研究显示，在p85缺失的情况下，DC和常见DC祖细胞（CDPs）的增殖增加，p85突变DC亚群对Flt3L的反应改变了信号转导途径。从本质上讲，这里的数据首次明确地确立了IA类pi3k的P85α亚基在DCs的发展和维持中具有不可或缺的作用。
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 IA 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 IA PI3Ks has an indispensable role in the development and maintenance of DCs.
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影响因子：
30.5
作者：
Fukao, T;Tanabe, M;Koyasu, S
通讯作者：
Koyasu, S
DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
8
作者：
Hemmati, Shayda;Sinclair, Taneisha;Gritsman, Kira
通讯作者：
Gritsman, Kira
DOI：
10.1126/science.1170540
发表时间：
2009-04-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Liu K;Victora GD;Schwickert TA;Guermonprez P;Meredith MM;Yao K;Chu FF;Randolph GJ;Rudensky AY;Nussenzweig M
通讯作者：
Nussenzweig M