(The FASEB Journal. 2008;22:662.6)
© 2008 FASEB
(The FASEB Journal. 2008;22:662.6.)
© 2008 FASEB
The interdependent role of YMNM and PxxP motifs in CD28 costimulation
Shuhei Ogawa1,
Hidehiro Kishimoto2 and
Ryo Abe3
1 Division of Immunobiology, Tokyo University of Science, Noda, Chiba, Japan
2 Division of Immunobiology, hidek{at}rs.noda.tus.ac.jp, Noda, chiba, Japan
3 Division of Immunobiology, rabe{at}rs.noda.tus.ac.jp, Noda, Chiba, Japan
ABSTRACT
CD28-mediated costimualtion is known to be critical required for T cell activation. There are Y189MNM motif and two PxxP motifs in CD28 cytoplasmic region that are thought to play a key role for the costimulatory function. It has been shown that the YMNM motif functions as a binding site for PI3K and Grb2/Gads, and the N-terminal and C-terminal PxxP motif play a critical role for binding to Itk and Lck. We generated transgenic mice expressing the Y->F mutant CD28 which lack both PI3K and Grb2/Gads binding and P->A mutant CD28 which lack binding of Lck and/or Itk in the CD28 deficient background. Previously, we reported that a point mutation of Y189 diminished proliferation and IL-2 production. In this study, we found that T cells from ncPA mutant mice which have mutations in both N- and C-terminal PxxP motifs showed striking defect in proliferation and IL-2 production similar to those from Y->F mutant. T cells from mice having individual mutation in N- or C-terminal PxxP motif demonstrated a defect of proliferative response to suboptimal dose of stimulation. These results suggested that both N- and C-terminal PxxP motifs are required for CD28 mediated costimulatory functions of T cell activation.
