Lelouard et al. With the ebb and flow of translation, antigen-presenting dendritic cells (DCs) adjust the origin of their antigens.
DCs are professional immunity activators that alert T cells to the presence of invaders by displaying antigens on their surface. This display is ramped up by a maturation program initiated when a DC encounters inflammatory stimuli such as pathogenic components. Scientists have identified an abundance of transcriptional changes that take place during maturation. The new results show that a boost in translation is necessary to put the new transcripts into action.
Translation peaked in DCs about 4 hours after their activation. During this stretch, translation—and the PI3K/AKT/mTOR signaling pathway that activated it—was needed for maturation-associated changes in the DCs. These changes include producing T cell-activating cytokines and activating the antigen-presenting machinery.
After 4 to 8 hours, protein synthesis levels declined, due at least in part to proteasome-mediated cleavage of the eIF4GI translation initiation factor. At 16 hours, overall translation levels were even lower than they were before activation.
Some transcripts, however, escaped the translation shutdown. As also occurs during stress conditions, eIF4GI cleavage initiated an unusual translation pathway that bypasses the need for a 5′ cap on transcripts. Cap-independent translation, which favors the synthesis of antiapoptotic proteins, made mature DCs resistant to apoptosis-inducing drugs. This pathway might thus help activated DCs survive the stress of their heavy new transcription and translation loads while they search for and then activate T cells.
As DCs switched translation pathways, they also changed the source of antigens presented on MHC class I molecules. During the early, translation-heavy stage, antigens were derived from pieces of newly synthesized proteins; when the authors blocked translation, antigen presentation was limited. But later on, translation inhibitors did not interfere with MHC class I presentation.
The authors speculate that once DCs have matured, their antigens are mainly derived from exogenous sources, such as pathogens. Although normally presented on MHC class II molecules, exogenous peptides can also crossover to the class I pathway. An alternative possibility is that late antigens come from a pool of stored, presynthesized self-peptides.