classically , major histocompatibility complex ( mhc ) class i molecules present intracellular antigens to cd8 t cells and mhc class ii molecules present extracellular antigens to cd4 t cells during adaptive immune responses . however , professional antigen - presenting cells , such as dendritic cells ( dcs ) , can process extracellular antigen for mhc class i presentation by a pathway called cross - presentation . vice versa , fragments of nuclear and cytosolic antigens have been found among natural mhc class ii ligands , and it has been shown that some antigens can be presented by mhc class ii after intracellular processing . some of these use autophagy to gain access to lysosomal degradation in mhc class ii loading compartments [ 6 - 10 ] . primarily , one particular autophagic pathway , called macroautophagy , has been implicated in intracellular antigen processing for mhc class ii presentation to cd4 t cells . during macroautophagy an isolation membrane , which is thought to have originated from rough endoplasmic reticulum , the outer nuclear envelope membrane or the outer mitochondrial membrane [ 11 - 15 ] , engulfs cytoplasmic constituents such as damaged organelles , protein aggregates and pathogens . two ubiquitin - like systems with the atg8 and atg12 proteins at their heart are involved in extension of the autophagosomal membrane and substrate recruitment to its interior [ 16 - 18 ] . upon completion of the resulting double membrane - surrounded autophagosome , these proteins are removed from the outer autophagosomal membrane , which then allows the fusion with lysosomes and late endosomes , such as multivesicular bodies ( mvbs ) . the inner autophagosomal membrane and the autophagosome cargo . a subset of mvbs , known as mhc class ii loading compartments , is used for antigen loading of mhc class ii molecules . autophagosomes fuse quite efficiently with these vesicles , resulting in mhc class ii presentation of the autophagic cargo . thus , macroautophagy can deliver cytoplasmic antigens for mhc class ii presentation to cd4 t cells . in addition to the mechanistically fairly plausible intracellular antigen processing onto mhc class ii molecules via macroautophagy , recent studies have also suggested that macroautophagy might assist with extracellular antigen processing for mhc class i and class ii presentation . with respect to cross - presentation , two studies have demonstrated that viral and tumor antigens are more efficiently presented in trans to cd8 t cells when the antigen donor cell can perform macroautophagy . in the first of these studies , apoptosis - deficient mouse embryonic fibroblasts ( bax / bak mefs ) were more efficiently cross - presented after influenza a virus infection than wild - type mefs . this cross - presentation was inhibited by small interfering rna ( sirna)-mediated silencing of the essential macroautophagy gene product atg5 . in a second study , cross - presentation of the model antigen ovalbumin and the melanocyte differentiation antigen gp100 was diminished when macroautophagy was compromised in the antigen - donating epithelial and melanoma cell lines via sirna knockdown of atg6 and atg12 . these studies suggest that macroautophagy assists in the packaging of antigens for efficient cross - presentation . in addition , macroautophagy seems to also facilitate the transport of endocytosed antigen to lysosomes for degradation as well as facilitating their loading onto mhc class ii molecules . enhanced delivery of phacocytosed material to lysosomes with the assistance of the molecular macroautophagy machinery was first described after toll - like receptor 2 ( tlr 2 ) stimulation of murine macrophages . this pathway also delivered salmonella - encoded antigens for mhc class ii presentation and was sensitive to sirna - mediated silencing of atg5 , atg7 and atg16l1 . interestingly , mutations in nod2 and atg16l1 , which predispose for crohn 's disease , also compromise both bacterial clearance and mhc class ii presentation of bacterial antigens to cd4 t cells . along the same lines , atg5-deficient dcs are compromised in priming cd4 t cell responses after herpes simplex virus infection and in efficiently processing extracellular ovalbumin for mhc class ii presentation . at the same time , priming of cd8 t cell responses and cross - presentation on mhc class i are not affected . finally , hiv infection of dcs seems to inhibit macroautophagy in order to increase virus production and to prevent viral antigen presentation to cd4 t cells . macroautophagy stimulation enhances , whereas sirna - mediated silencing of atg5 and atg8 decreases , hiv antigen presentation on mhc class ii but not on mhc class i molecules . altogether , these data suggest that macroautophagy facilitates endosome cargo delivery for lysosomal degradation , which results in increased extracellular antigen processing for mhc class ii presentation to cd4 t cells . autophagosomes , which form isolation membranes around cytoplasmic constituents , fuse with mhc class ii loading compartments ( miics ) , which are a subset of multivesicular bodies ( mvbs ) . autophagosomes fuse with mvbs either directly or after fusion with endosomes ( forming amphisomes ) . autophagic cargo can also escape from the mvbs via exocytosis and can then be efficiently cross - presented by dendritic cells ( dcs ) . in light of these recent advances , it has become clear that macroautophagy regulates antigen presentation by mhc molecules beyond just intracellular antigen processing for cd4 t cell stimulation . however , the mechanisms of antigen packaging by macroautophagy for cross - presentation and macroautophagy - mediated acceleration of endosome degradation by lysosomes remain elusive . in antigen donor cells , macroautophagy could provide the necessary energy to decorate dying cells with ligands for phagocytosis , such as , for example , phosphatidylserine , which needs to be flipped from the inner to the outer cell membrane leaflet in order to become an  eat - me signal . alternatively , autophagosome cargo could also be more efficiently released from mvbs via an alternative secretion pathway recently reported for the yeast pichia pastoris and the slime mold dictyostelium discoideum . with respect to macroautophagic assistance for endosome fusion with lysosomes , it first needs to be clarified whether this represents an alternative use of atgs , independent of macroautophagy , as was initially proposed , or whether amphisomes , the fusion vesicles between autophagosomes and endosomes , get targeted more rapidly to lysosomes . in a second step , the molecular basis for this enhanced targeting then needs to be elucidated . irrespective of the mechanism , macroautophagic support for endosome fusion with lysosomes could explain why tlr coating increases antigen processing for mhc class ii presentation . although much more needs to be done to characterize the underlying mechanisms , the recent studies discussed in this report suggest novel and exciting pathways in immunology , and cell biology in general , by which macroautophagy regulates endocytosis and exocytosis , in addition to its classical function in the degradation of cytoplasmic constituents by lysosomes .
autophagy delivers cytoplasmic constituents for lysosomal degradation . 
 this catabolic pathway can be used to deliver intracellular antigens for major histocompatibility complex ( mhc ) class ii presentation . in addition 
 , recent evidence suggests that it also facilitates the processing of extracellular antigens for both mhc class i and ii presentation .