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with a Lipid Raft-Associated Inhibitor of 
B Factor Kinase (IKK) Complex Plays a Role in the Activation of the NF-B Cascade by TCR and CD281
Division of Clinical Immunology and Allergy, Department of Medicine, Center for Health Sciences, University of California, Los Angeles, CA 90095
We investigated the role of protein kinase C 
(PKC) in the
activation of the NF-
B cascade in primary human CD4+
lymphocytes. Among six or so PKC isoforms expressed in T cells, only
PKC participates in the assembly of the supramolecular activation
clusters at the contact site of the TCR with Ag. Signaling via both the
TCR and CD28 is required for optimal activation of the multisubunit
IB kinase (IKK) complex in primary human T lymphocytes; this
activation could be inhibited by a Ca2+-independent PKC
isoform inhibitor, rottlerin. Moreover, endogenous PKC physically
associates with activated IKK complexes in CD3/CD28-costimulated
primary CD4+ T cells. The same set of stimuli also induced
relocation of endogenous PKC and IKKs to a GM1 ganglioside-enriched,
detergent-insoluble membrane compartment in primary T cells. IKKs
recruited to these lipid rafts were capable of phosphorylating a
recombinant IB
sustrate. Confocal microscopy further demonstrated
that exogenously expressed PKC and IKKß colocalize in the membrane
of CD3/CD28-costimulated Jurkat T cells. Constitutively active but not
kinase-inactive PKC activated IKKß in Jurkat T cells. Expression
of dominant-active PKC also had stimulatory effects on the CD28
response element of the IL-2 promoter. Taken together, these data show
that the activation of PKC by the TCR and CD28 plays an important
role in the assembly and activation of IKK complexes in the T cell
membrane.
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