Apoptosis: Assembly blocked

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New work reports a direct role for CD28 in preventing Fas-mediated apoptosis, by activating protein kinase B/Akt and preventing the assembly of the death-inducing signaling complex.

The T-cell co-stimulatory molecule CD28 promotes T-cell activation and survival. However, the mechanisms by which CD28 signalling boosts cell survival are poorly understood. Work from Jones and colleagues published in The Journal of Experimental Medicine reports a direct role for CD28 in preventing Fas-mediated apoptosis, by activating protein kinase B (PKB)/Akt and preventing the assembly of the death-inducing signalling complex (DISC).

The physiological importance of the Fas (CD95)–Fas ligand (FasL, CD178) apoptotic pathway is clear from studies of lpr and gld mice — naturally occurring mutants of Fas and FasL, respectively — which develop systemic autoimmunity. To investigate the influence of CD28 signalling on Fas-mediated apoptosis, the authors used various transgenic and gene-deficient mice.

First, they showed that CD4⁺ T cells from Cd28^-/- mice are more susceptible to Fas-mediated cell death than those from wildtype mice. Then, they showed that the activation of phosphatidylinositol 3-kinase (PI3K), an important signalling molecule that is recruited by CD28, is required for CD28-mediated protection against Fas-induced apoptosis, because Cd28^-/- mice that express a mutant Cd28 transgene that cannot bind to PI3K are as susceptible to Fas-mediated apoptosis as the Cd28^-/- mice.

Previous studies have shown that the serine/threonine kinase PKB is activated in a PI3K-dependent manner downstream of CD28, so Jones and colleagues analysed Fas–FasL-mediated apoptosis in transgenic mice that express active PKB alpha in T cells. Fas-mediated apoptosis was impaired in PKB alpha -expressing T cells in vitro and in vivo. Further analysis of the Fas–FasL apoptotic cascade showed that the activation of caspase-8, BID and caspase-3 is impaired in these transgenic T cells, because recruitment of procaspase-8 to the DISC is blocked.

These data provide genetic evidence of a survival role for CD28-dependent PKB signalling in preventing Fas-mediated apoptosis by blocking DISC assembly.

Jenny Buckland

References

Jones, R. G. et al. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J. Exp. Med. 196, 335–348 (2002) | PubMed |