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 secreti on 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 super family death domain-containing molecule, death receptor (DR)6, which potent ly activates JNK. T cells from DR6-deficient mice are substantially impaire d in JNK activation. When DR6(-/-) mice were challenged with protein antige n, their T cells hyperproliferate and display a profound polarization towar d 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 apoptot ic pathway. Therefore, DR6, working through JNK, rather than apoptosis, fun ctions 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.