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The interdependent role of YMNM and PxxP motifs in CD28 costimulation
Author(s) -
Ogawa Shuhei,
Kishimoto Hidehiro,
Abe Ryo
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.662.6
Subject(s) - cd28 , mutant , microbiology and biotechnology , t cell , chemistry , t cell receptor , biology , biochemistry , immunology , immune system , gene
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.