Delta-like 4 differentially regulates murine CD4 T cell expansion via BMI1.
BACKGROUND
Studies have shown that Notch is essential for the maintenance of a T cell Th2 phenotype in vivo. It has also been shown that Notch ligands have diverse functions during T cell activation. We chose to investigate the role of Notch ligands during the Th2 response.


RESULTS
We studied the relationship of two Notch ligands, delta-like 4 and jagged-1, to T cell proliferation in C57 Bl/6 mice. Our findings indicate that jagged-1 does not affect the rate of T cell proliferation in any subset examined. However, delta-like 4 causes an increase in the expansion of Th2 memory cells and a decrease in effector cell proliferation. Our in vivo studies indicate that the Notch system is dynamically regulated, and that blocking one Notch ligand increases the effective concentration of other Notch ligands, thus altering the response. Examination of genes related to the Notch pathway revealed that the Notch receptors were increased in memory T cells. Expression of BMI1, a gene involved in T cell proliferation, was also higher in memory T cells. Further experiments demonstrated that Notch directly regulates the expression of the BMI1 gene in T cells and may govern T cell proliferation through this pathway.


CONCLUSIONS
From these experiments we can make several novel conclusions about the role of Notch ligands in T cell biology. The first is that delta-like 4 suppresses effector cell proliferation and enhances Th2 memory cell proliferation. The second is that blocking one Notch ligand in vivo effectively increases the concentration of other Notch ligands, which can then alter the response.
Schaller
Matthew A
MA
Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America. mschalle@umich.edu
Logue
Hannah
H
Mukherjee
Sumanta
S
Lindell
Dennis M
DM
Coelho
Ana Lucia
AL
Lincoln
Pamela
P
Carson
William F
WF
Ito
Toshihiro
T
Cavassani
Karen A
KA
Chensue
Stephen W
SW
Hogaboam
Cory M
CM
Lukacs
Nicholas W
NW
Kunkel
Steven L
SL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C489421:Bmi1 protein, mouse; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D063150:Polycomb Repressive Complex 1
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