Inhibitory Signals from a TNF Receptor

Abstract

T cell activation occurs upon the stimulation of the T cell receptor and secondary costimulatory proteins (see the Connections Map by Koretzky and Singer for details about T cell receptor signaling). The costimulatory signal can be provided by one of several ligand-receptor interactions, including members of the tumor necrosis factor (TNF) family. Liu et al. discovered a negative signal for T cell proliferation that is transmitted through the death domain-containing receptor DR6 of the TNF receptor family by analyzing the proliferative responses of T cells from DR6 -deficient mice. Both in isolated T cells and in cells from antigen-challenged mice, disruption of DR6 led to hyperproliferation of T cells. DR6 -/- CD4 + T cells demonstrated enhanced proliferation in response to T cell activation that did not involve increased production of interleukin 2 (IL-2). However, activated DR6 -/- T cells did express higher levels of the costimulatory protein CD28 and the IL-2 receptor α subunit CD25 and exhibited higher proliferative response to exogenously added IL-2 than to wild-type T cells. Confirmation of an inhibitory signal was obtained by inhibiting the DR6 ligand-receptor interaction with soluble DR6, which produced hyperproliferation in wild-type T cells. DR6 -/- CD4 + T cells stimulated by activation of the TCR and the CD28 complex, there was enhanced secretion of T helper cell type 2 (Th2) cytokines compared with wild-type T cells, suggesting that DR6 provides a negative signal regulating Th2 differentiation. The results presented by Liu et al. are important for understanding the mechanisms controlling T cell differentiation and proliferation and are an example of how activation of a TNF receptor provides an inhibitory signal regulating cell proliferation. J. Liu, S. Na, A. Glasebrook, N. Fox, P. J. Solenberg, Q. Zhang, H. Y. Song, D. D. Yang, Enhanced CD4 + T cell proliferation and Th2 cytokine production in DR6 -deficient mice. Immunity 15 , 23-34 (2001). [Online Journal] G. Koretzky, A. Singer, T cell signal transduction. Science's STKE (Connections Map, as seen July 2001), http://stke.sciencemag.org/cgi/cm/CMP_7019. [Pathway]