Delta-like 4 differentially regulates murine CD4+ T cell expansion via BMI1

Abstract

Background: Studies have shown that Notch is essential for the maintenance of a T cell Th2 phenotype in vivo. It has alsobeen shown that Notch ligands have diverse functions during T cell activation. We chose to investigate the role of Notchligands during the Th2 response. Principal Findings: We studied the relationship of two Notch ligands, delta-like 4 and jagged-1, to T cell proliferation inC57 Bl/6 mice. Our findings indicate that jagged-1 does not affect the rate of T cell proliferation in any subsetexamined. However, delta-like 4 causes an increase in the expansion of Th2 memory cells and a decrease in effectorcell proliferation. Our in vivo studies indicate that the Notch system is dynamically regulated, and that blocking oneNotch ligand increases the effective concentration of other Notch ligands, thus altering the response. Examination ofgenes related to the Notch pathway revealed that the Notch receptors were increased in memory T cells. Expression ofBMI1, a gene involved in T cell proliferation, was also higher in memory T cells. Further experiments demonstrated thatNotch directly regulates the expression of the BMI1 gene in T cells and may govern T cell proliferation through thispathway. Conclusions: From these experiments we can make several novel conclusions about the role of Notch ligands in T cellbiology. The first is that delta-like 4 suppresses effector cell proliferation and enhances Th2 memory cell proliferation. Thesecond is that blocking one Notch ligand in vivo effectively increases the concentration of other Notch ligands, which canthen alter the response. © 2010 Schaller et al.