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Original Article |
Address correspondence to Vishva M. Dixit, Dept. of Molecular Oncology, Genentech Inc., 1 DNAWay, MS40, South San Francisco, CA 94080. Phone: 650-225-1312; Fax: 650-225-6127; E-mail: dixit{at}gene.com
During an immune response naive T helper (Th) cells differentiate into two functionally distinct subsets, Th1 and Th2, based on their cytokine secretion profile and immunomodulatory function. c-Jun amino terminal kinase (JNK) regulates Th cell differentiation by activating a transcriptional program required for cytokine production. We have recently identified a TNFR superfamily death domain–containing molecule, death receptor (DR)6, which potently activates JNK. T cells from DR6-deficient mice are substantially impaired in JNK activation. When DR6-/- mice were challenged with protein antigen, their T cells hyperproliferate and display a profound polarization toward a Th2 response whereas Th1 differentiation is not equivalently affected. In addition, DR6-/- T cells showed preference toward Th2 differentiation in vitro. The phenotype seen in the DR6-/- mice is not due to the apoptotic pathway. Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response. This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.
Key Words: hyperproliferation • apoptosis • TNFR-superfamily • polarization • Th2
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