Abstracts (complete list) - Wissenschaft Online

Anette J. Bauer, Katharina M. Huster, Verena Labi, Roland M. Schmid, Dirk H. Busch,
Andreas Villunger, Georg Häcker
Several members of the mitochondrial apoptosis pathway
control activated T cell death to terminate the T cell immune
response
Stimulation of APC by adjuvants is an important step in development of an effective
immune response through the upregulation of costimulatory molecules and the release
of cytokines. Previous work has shown that stimulation of dendritic cells by adjuvant
can reduce cell death of activated T cells at the end of the response. Furthermore, it has
been shown that this cell death requires the pro-apoptotic protein Bim and is blocked by
Bcl-2 expression in T cells. In this study we investigated the interrelations of proteins
implicated in the regulation of this activated T cell death. TLR ligands present during
stimulation of spleen cell populations or in vivo prolonged the survival of activated T
cells, an activity that was mimicked by DC-derived factors or the presence of IL-1, IL-7
or IL-15. Bcl-2-transgenic T cells showed better survival than bim-/--cells, and DCderived
factors increased the survival of bim-/--T cells, indicating a Bim-independent
pathway. This pathway was found largely to be regulated by the pro-apoptotic Bcl-2
protein Puma, possibly with a marginal contribution from Noxa. The NF-kappa B
regulator Bcl-3 was involved upstream of the activity of Bim and had an anti-apoptotic
effect. Bim and Puma appeared to be regulated by similar molecular activation
pathways as DC-derived cytokines were able to delay the activation of both. Expression
analysis showed a strong divergence of Bim expression and –activity, strongly
suggesting post-translational regulation of Bim. Additional experiments examining
function of antigen specific Bcl-2 transgenic T cells during Listeria infection in vivo show
that Bcl-2 not only blocks death but also conserves function of T cells at the end of the
immune reaction. Thus, apoptosis of activated T cells at the end of an acute immune
response is a process regulated by members of the mitochondrial apoptosis pathway
that is instrumental in switching off the immune response.