PMID- 35853935
OWN - NLM
STAT- MEDLINE
DCOM- 20220721
LR  - 20230601
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jul 19
TI  - Class I PI3K regulatory subunits control differentiation of dendritic cell 
      subsets and regulate Flt3L mediated signal transduction.
PG  - 12311
LID - 10.1038/s41598-022-16548-x [doi]
LID - 12311
AB  - 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 (p110delta and p110gamma) 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-p85alpha and p85beta of the Class I(A) 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 P85alpha subunit of class I(A) PI3Ks has an indispensable role in 
      the development and maintenance of DCs.
CI  - (c) 2022. This is a U.S. Government work and not under copyright protection in the 
      US; foreign copyright protection may apply.
FAU - Thummar, Keyur
AU  - Thummar K
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY, 10032, USA.
FAU - Rathinam, Chozha Vendan
AU  - Rathinam CV
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY, 10032, USA. crathinam@ihv.umaryland.edu.
AD  - Institute of Human Virology, University of Maryland School of Medicine, 725 West 
      Lombard Street, Baltimore, MD, 21201, USA. crathinam@ihv.umaryland.edu.
AD  - Center for Stem Cell and Regenerative Medicine, University of Maryland School of 
      Medicine, 725 West Lombard Street, Baltimore, MD, 21201, USA. 
      crathinam@ihv.umaryland.edu.
LA  - eng
GR  - R01 HL132194/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220719
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Membrane Proteins)
RN  - 0 (flt3 ligand protein)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/immunology
MH  - Cell Differentiation/immunology
MH  - *Class I Phosphatidylinositol 3-Kinases/immunology
MH  - *Dendritic Cells/enzymology/immunology
MH  - *Membrane Proteins/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Signal Transduction/immunology
PMC - PMC9296662
COIS- The authors declare no competing interests.
EDAT- 2022/07/20 06:00
MHDA- 2022/07/22 06:00
PMCR- 2022/07/19
CRDT- 2022/07/19 23:21
PHST- 2022/03/05 00:00 [received]
PHST- 2022/07/12 00:00 [accepted]
PHST- 2022/07/19 23:21 [entrez]
PHST- 2022/07/20 06:00 [pubmed]
PHST- 2022/07/22 06:00 [medline]
PHST- 2022/07/19 00:00 [pmc-release]
AID - 10.1038/s41598-022-16548-x [pii]
AID - 16548 [pii]
AID - 10.1038/s41598-022-16548-x [doi]
PST - epublish
SO  - Sci Rep. 2022 Jul 19;12(1):12311. doi: 10.1038/s41598-022-16548-x.