Submitted December 3, 2008
Accepted April 24, 2009
Regulation of Th17 cell differentiation and EAE induction by the MAP3K NIK
Wei Jin, Xiao-Fei Zhou, Jiayi Yu, Xuhong Cheng, and Shao-Cong Sun*
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: ssun{at}mdanderson.org.
Th17 cells play an important role in mediating autoimmune diseases, but the molecular mechanism underlying Th17 differentiation is incompletely understood. We show here that NF-
B inducing kinase (NIK), which is known to regulate B-cell maturation and lymphoid organogenesis, is important for the induction of Th17 cells. NIK-deficient naive CD4 T cells are attenuated in the differentiation to Th17 cells, although they are competent in committing to the other effector lineages. Consistently, NIK knockout mice are resistant to experimental autoimmune encephalomyelitis, a disease model that involves the function of Th17 cells. This phenotype was also detected in Rag2 knockout mice reconstituted with NIK-deficient T cells, confirming a T-cell intrinsic defect. We further show that NIK mediates synergistic activation of STAT3 by the T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates the activation of STAT3 and the induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and EAE induction.
