Thursday March 22 from 14.00 to 15.00, Point Centre, Auditorium Albert Claude
Common seminar IBMM-IMI with Philippe Pierre, Centre d'Immunologie de Marseille-Luminy, INSERM U1104, Marseille, France
"Microbial detection controls antigen degradation by autophagy and subsequent endogenous MHC II-restricted presentation in dendritic cells."
Dendritic cells (DCs) are antigen presenting cells with the unique capacity to initiate primary immune responses. DCs have a remarkable pattern of differentiation (maturation) that exhibits highly specific mechanisms to control antigen presentation in response to microbial stimuli. In particular, expression, transport and loading of MHC class I and II molecules are strongly activated during DC maturation. MHC class I molecules present to CD8+ cytotoxic T cells peptides mostly derived from defective cytosolic proteins (DRiPS), which are ubiquitinated and degraded by the proteasome. Here, we show that newly synthesized defective proteins are also targeted to autophagosomes and degraded. Upon DC maturation, autophagy is inhibited leading to the accumulation of these DRiPs in large cytosolic structures. Interestingly, these Dendritic cell Aggresome Like Induced Structures (DALIS) are transient, and require both translation inhibition and proteasome activity for their disapearance. Thus, autophagy affects the efficiency of the classical proteasome-mediated antigen processing by competing for a fraction of the same DRiPs substrates. Autophagy was estimated to reduce the level MHC I presentation by 20%. We also demonstrate, that this pathway is used by DCs to present endogenous proteins on the MHC II molecules and that immature cells have the capacity of presenting peptides derived from the same endogenous antigens both on the MHC I and MHC II. Upon microbial activation MHC II presentation of the endogenous antigens is lost, while the MHC I antigens source changes from newly synthesized proteins to other undefined sources. Morever, we demonstrate that several cytokines can revert this process and induce alternative pathways for the autophagic processing of antigens as well as different immunological functions.