Functional analysis of the non-HLA genes within major histocompatibility complex (MHC) region with the use of gene-targeted mice

点击翻译按钮获取中文摘要

NF-Kb-inducting kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-b receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and co atimulation pahways, 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 respones to anti-CD3 stim ulation, and these effects were caused by impaired NF-Kb activity in both mature and immature T cells; the impaired NF-Kb. In contrast, responses to co- stimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the co-stim ulatory 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-Kb 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.