Journal
BLOOD
Volume 113, Issue 26, Pages 6603-6610Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-12-192914
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Funding
- NIAID NIH HHS [AI057555, R01 AI057555, R37 AI064639, AI064639, R01 AI064639] Funding Source: Medline
- NIGMS NIH HHS [GM084459, R01 GM084459] Funding Source: Medline
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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-kappa 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 T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates activation of STAT3 and induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and experimental autoimmune encephalitis induction. (Blood. 2009; 113: 6603-6610)
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