Essential role of NF-kappa B-inducing kinase in T cell activation through the TCR/CD3 pathway.
NF-kappa B-inducing kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-beta 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-kappa B activity in both mature and immature T cells; the impaired NF-kappa B activity in mature T cells was also associated with the failure of maintenance of activated NF-kappa 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-kappa 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.
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan. mitsuru@ier.tokushima-u.ac.jp
Mitsuru
M
Matsumoto
Takuji
T
Yamada
Steven K
SK
Yoshinaga
Tom
T
Boone
Tom
T
Horan
Shigeru
S
Fujita
Yi
Y
Li
Tasuku
T
Mitani
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D051550:I-kappa B Kinase; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors; D000097782:NF-kappaB-Inducing Kinase
D000081242:B-Cell Lymphoma 3 Protein; D051550:I-kappa B Kinase; D007376:Interleukin-2; D016328:NF-kappa B; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D000097782:NF-kappaB-Inducing Kinase; C000631345:Bcl3 protein, mouse; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse