Interestingly this situation might be changed by the

Interestingly, this situation might be changed by the immunological context, in particular by the cytokines encountered during differentiation or activation. LPS-activation of bone marrow-derived DCs differentiated in GM-CSF decreases autophagy, CP2, and subsequent activation of CD4+ T cells (Fig. 2). However, presence of IL-4 during differentiation inverts this situation by promoting autophagy and enhancing the processing and presentation of endogenous Cisplatin via CP2 (Fig. 2) (Terawaki et al., 2015). Similarly, primary human monocyte-derived DC with IL4 are inefficient at forming DALIS upon autophagy inhibition (Montagna et al., 2017), while they are enriched in proteasome-containing particulate cytoplasmic structures (PaCS) (Necchi et al., 2010). IL4 also induces autophagy in murine B cells and promotes increased MHC II antigen presentation, which correlates with exacerbated asthma (Xia et al., 2018). These data demonstrate that antigen processing regulation is extremely dynamic and CP2 can be reprogrammed by the microenvironment in which APCs evolve.
Other sources of intracellular antigens for CP2 Autophagy is also an important process to eliminate invading intracellular microorganisms (xenophagy) (Cadwell, 2016), as well as damaged organelles, such as ruptured phagosomes, preventing ingested bacteria or viruses to invade the cell, and favouring their processing for MHC II presentation (Thurston et al., 2012). Xenophagy protects cells from infection, despite the fact that many intracellular microbe species have learned to tweak autophagy for their own benefit (Winchell et al., 2016). Bacterial clearance can occur during autophagy of ruptured phagosomes or by directly engulfing bacteria in the cytosol. The surface of bacteria entering the cytoplasm gets ubiquitinated (Huett et al., 2012; Tumbarello et al., 2015), providing a substrate for NDP52, optineurin, or TAX1BP1 binding and tagging the microbes for engulfment and destruction by autophagosomes (Perrin et al., 2004; Thurston et al., 2009; Tumbarello et al., 2015; Wild et al., 2011). NDP52 can also bind to galectin 3 and 8, lectins detecting the abnormal appearance of glycosylated proteins in the cytoplasm upon accidental or pathogenic rupture of endosomes or phagosomes (Thurston et al., 2012). Increased autophagy, required to limit cell susceptibility to infection, is achieved by optimizing autophagy effector protein activity and organelle distribution. Interestingly, xenophagy shows many parallels with mitophagy, a form of autophagy that disposes of damaged, depolarized mitochondria. An example of this parallelism is observed during IL4-induced DC differentiation that facilitates clearance of both damaged mitochondria and intracellular bacteria (Terawaki et al., 2015). Enhanced mitophagy also facilitates presentation of mitochondrial antigens by DCs. This presentation occurs mostly in tolerogenic conditions, since the production of reactive oxygen species (ROS) by damaged mitochondria and subsequent NALP3 inflammasome activation are decreased by upregulation of autophagy in non-activated DCs (Nakahira et al., 2011). The mitochondria-associated kinase PINK1 activates the ubiquitin ligase Parkin to recruit the autophagy receptors NBR1 and optineurin, directing mitochondria towards autophagic degradation (Heo et al., 2015; Lazarou et al., 2015). Interestingly, PINK1 and Parkin deficiency leads to accumulation of mitochondrial antigens that are then more readily available for antigen presentation. Consequently, genetic mutations affecting PINK1 and Parkin in patients with Parkinson’s disease lead to abnormal presentation of endogenous antigens and induction of adaptive immunity, making Parkinson’s an autoimmune disease (Matheoud et al., 2016). Anti-mitochondrial antibodies also play an important role in the development of primary biliary cirrhosis (Fritzler and Manns, 2002), indicating that uncontrolled processing and presentation of mitochondrial antigens can be deleterious in different and apparently unrelated pathologies.