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* Department of Microbiology and Brain, Korea 21 Project of Medical Sciences, Yonsei University College of Medicine, Seoul, Korea; and Departments of
Microbiology and
Anatomy, Pochon Cha University College of Medicine, Kyunggi-Do, Korea
In this study we investigated the molecular mechanism of the
activation-induced cell death (AICD) inhibition mediated by a p70
inhibitory killer cell Ig-like receptor (KIR3DL1, also called NKB1) in
Jurkat T cells. Using stable Jurkat transfectants that express KIR or
CD8-KIR fusion proteins we have shown for the first time that KIR
inhibits, in a ligation-independent manner, the AICD induced by PHA,
PMA/ionomycin, or anti-CD3 Ab. The AICD inhibition mediated by KIR
appears to result from the blockade of Fas ligand induction upon
activation of the Jurkat transfectants. Moreover, the membrane-proximal
20 aa of the KIR cytoplasmic tail were determined to play a crucial
role in this process. Since the membrane-proximal portion of the KIR
cytoplasmic tail contains a putative protein kinase C (PKC) substrate
site, we investigated the molecular interaction between KIR and PKC.
Immunoprecipitation analysis demonstrated that KIR constitutively bound
both to PKC
, a conventional Ca2+-dependent PKC, and to
PKC
, a novel Ca2+-independent PKC. Furthermore, an in
vitro kinase assay revealed that PKC activation was blocked after PHA
stimulation in Jurkat transfectants expressing KIR. These observations
were supported by the finding that a recombinant KIR cytoplasmic tail
also appeared to inhibit PKC activation in vitro. Taken together
these data strongly suggest that KIR inhibits the AICD of T cells by
blocking Fas ligand induction upon stimulation, in a process that seems
to be accomplished by PKC recruitment to the membrane-proximal PKC
binding site and subsequent inhibition of PKC activation against the
activating stimuli.
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