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B-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway1
* Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan;
First Department of Internal Medicine, School of Medicine, Ehime University, Ehime, Japan; and
Amgen, Thousand Oaks, CA 91320
NF-
B-inducing kinase (NIK) is involved in lymphoid organogenesis
in mice through lymphotoxin-
receptor signaling. To clarify the
roles of NIK in T cell activation through TCR/CD3 and costimulation
pathways, we have studied the function of T cells from
aly mice, a strain with mutant NIK. NIK mutant T cells
showed impaired proliferation and IL-2 production in response to
anti-CD3 stimulation, and these effects were caused by impaired
NF-B activity in both mature and immature T cells; the impaired
NF-B activity in mature T cells was also associated with the failure
of maintenance of activated NF-B. In contrast, responses to
costimulatory signals were largely retained in aly mice,
suggesting that NIK is not uniquely coupled to the costimulatory
pathways. When NIK mutant T cells were stimulated in the presence of a
protein kinase C (PKC) inhibitor, proliferative responses were
abrogated more severely than in control mice, suggesting that both NIK
and PKC control T cell activation in a cooperative manner. We also
demonstrated that NIK and PKC are involved in distinct NF-B
activation pathways downstream of TCR/CD3. These results suggest
critical roles for NIK in setting the threshold for T cell activation,
and partly account for the immunodeficiency in aly
mice.
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