Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice.
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.
Zhao
H
H
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Yan
M
M
Wang
H
H
Erickson
S
S
Grewal
I S
IS
Dixit
V M
VM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D003001:Cloning, Molecular; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008969:Molecular Sequence Data; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D007073:Immunoglobulin E; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases