The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published 12 November 2001. doi:10.1084/jem.194.10.1441
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© Rockefeller University Press, 0022-1007/2001/11/1441/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 10, November 19, 2001 1441-1448

Original Article

Impaired c-Jun Amino Terminal Kinase Activity and T Cell Differentiation in Death Receptor 6–deficient Mice

Haoran Zhao1, Minhong Yan1, Hua Wang2, Sharon Erickson1, Iqbal S. Grewal2 and Vishva M. Dixit1

1 Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080
2 Department of Immunology, Genentech Inc., South San Francisco, CA 94080

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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