Sci. Signal., 23 June 2009
Degrading the GatekeeperFull activation of T cells in vivo requires the simultaneous delivery of two independent signals: stimulation of the T cell receptor (TCR) by antigenic peptide presented by the major histocompatibility complex and stimulation of CD28 co-receptors. Stimulation of the TCR in the absence of a costimulatory signal results in a state of nonresponsiveness known as anergy, which is an important means of inhibiting the responses of self-reactive T cells that would otherwise trigger autoimmunity. The E3 ubiquitin ligase Cbl-b acts as a gatekeeper that prevents full activation of T cells by targeting proteins involved in TCR signaling for degradation (see the Perspective by Schmitz). Loss of cblb results in exacerbated autoimmune responses and enables activation of T cells through the TCR in the absence of costimulation of CD28. Cbl-b is itself targeted for ubiquitination and degradation in response to costimulation of CD28, but the mechanism involved is unclear. Gruber et al. found that protein kinase C- (PKC-), which is required for normal T cell immune responses, bound to Cbl-b on costimulation of CD28 and that PKC-–mediated phosphorylation of Cbl-b led to its ubiquitination and degradation. Experiments in which autoimmune disease was induced in mice singly or doubly deficient in cblb and PKC showed the antagonistic functions of Cbl-b and PKC- in regulating activation of T cells. Together, these data suggest that PKC- is critical for triggering the degradation of Cbl-b that is necessary to enable a full immune response in T cells.
Citation: T. Gruber, N. Hermann-Kleiter, R. Hinterleitner, F. Fresser, R. Schneider, G. Gastl, J. M. Penninger, G. Baier, PKC- Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation. Sci. Signal. 2, ra30 (2009).
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