PMID- 20038597
OWN - NLM
STAT- MEDLINE
DCOM- 20100217
LR  - 20211020
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 207
IP  - 1
DP  - 2010 Jan 18
TI  - Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase 
      activation by CXCR4.
PG  - 247-61
LID - 10.1084/jem.20091430 [doi]
AB  - T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with 
      contributions from both the class IA, p110delta, and class IB, p110gamma 
      catalytic subunits. However, the receptors on immature T cells by which each of 
      these PI3Ks are activated have not been identified, nor has the mechanism behind 
      their functional redundancy in the thymus. Here, we show that PI3K signaling from 
      the preTCR requires p110delta, but not p110gamma. Mice deficient for the class IB 
      regulatory subunit p101 demonstrated the requirement for p101 in T cell 
      development, implicating G protein-coupled receptor signaling in beta-selection. 
      We found evidence of a role for CXCR4 using small molecule antagonists in an in 
      vitro model of beta-selection and demonstrated a requirement for CXCR4 during 
      thymic development in CXCR4-deficient embryos. Finally, we demonstrate that 
      CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 
      thymocytes in the absence of supporting stromal cells. These findings establish a 
      role for CXCR4-mediated PI3K signaling that, together with signals from Notch and 
      the preTCR, contributes to continued T cell development beyond beta-selection.
FAU - Janas, Michelle L
AU  - Janas ML
AD  - Laboratory of Lymphocyte Signaling and Development, the Babraham Institute, 
      Babraham, Cambridge, CB22 3AT England, UK. michelle.janas@bbsrc.ac.uk
FAU - Varano, Gabriele
AU  - Varano G
FAU - Gudmundsson, Kristjan
AU  - Gudmundsson K
FAU - Noda, Mamiko
AU  - Noda M
FAU - Nagasawa, Takashi
AU  - Nagasawa T
FAU - Turner, Martin
AU  - Turner M
LA  - eng
GR  - BB/F02066X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - G0601618/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091228
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (CXCR4 protein, mouse)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcl12 protein, mouse)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Receptors, Notch)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - Animals
MH  - Catalytic Domain/physiology
MH  - Cell Line
MH  - Chemokine CXCL12/genetics/immunology/metabolism
MH  - Embryo, Mammalian/cytology/embryology/enzymology/immunology
MH  - Enzyme Activation/genetics/immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphatidylinositol 3-Kinases/genetics/*immunology/metabolism
MH  - Receptors, Antigen, T-Cell/genetics/immunology/metabolism
MH  - Receptors, CXCR4/genetics/*immunology/metabolism
MH  - Receptors, Notch/genetics/immunology/metabolism
MH  - Signal Transduction/*physiology
MH  - T-Lymphocytes/cytology/enzymology/*immunology
MH  - Thymus Gland/cytology/*embryology/enzymology/*immunology
PMC - PMC2812547
EDAT- 2009/12/30 06:00
MHDA- 2010/02/18 06:00
PMCR- 2010/07/18
CRDT- 2009/12/30 06:00
PHST- 2009/12/30 06:00 [entrez]
PHST- 2009/12/30 06:00 [pubmed]
PHST- 2010/02/18 06:00 [medline]
PHST- 2010/07/18 00:00 [pmc-release]
AID - jem.20091430 [pii]
AID - 20091430 [pii]
AID - 10.1084/jem.20091430 [doi]
PST - ppublish
SO  - J Exp Med. 2010 Jan 18;207(1):247-61. doi: 10.1084/jem.20091430. Epub 2009 Dec 
      28.