br Exocytosis of GLUT by autophagy br Conclusion br Conflict

Exocytosis of GLUT4 by autophagy
Conclusion
Conflict of interest
Ethics statement
Antigen processing and presentation Adaptive immune response has to be instructed to identify and eliminate specific pathogens or foreign entities defined by their antigenic determinants. Processed antigenic peptides are loaded on major histocompatibility complexes (MHC) and presented by professional antigen presenting cells (APC) to cognate T cells for priming and activation. MHC class II (MHC II) and its associated molecular machinery are naturally expressed by professional APC or upon exposure to interferon (IFN)-γ by other cells (Bania et al., 2003). One of the most prominent types of APCs are dendritic cells (DC), cells capable of orchestrating the immune response (Blum et al., 2013) by presenting antigenic peptides to naïve T cells. Recognition of peptides by these naïve T cells promotes their activation and initiates adaptive immune responses. Upon activation, T cells proliferate and differentiate into effector T cells, which migrate to inflamed tissues, where they exert their functions and contribute to the eradication of invading pathogens. MHC class I (MHC I) is expressed by all nucleated cell types and displays peptides to primed CD8+ cytotoxic T lymphocytes (CTL), which can kill target cells (e.g. tumours or virally infected cells) upon recognition of the right antigen-MHC combination (Blum et al., 2013). MHC I-restricted LKB1 originate predominantly from endogenous neosynthesized proteins (Fig. 1, green arrows). These intracellular antigens are processed by the proteasome into short peptides that are translocated by the TAP transporters into the lumen of the endoplasmic reticulum (ER) (Powis et al., 1991), where they can be loaded onto freshly translated MHC I complexes. Peptide-loaded MHC I complexes then follow the secretory pathway reaching the trans-Golgi network (TGN), from which they are mostly and directly addressed to the cell surface, while a minority reaches specific sorting endosomes, potentially serving cross-presentation of endocytosed antigens (De Angelis Rigotti et al., 2017; Nair-Gupta et al., 2014). Surface peptides/MHC I complexes displayed by activated DCs to naïve CTLs promote their proliferation and differentiation. These circulating CTLs, then, survey the occurrence of abnormalities in the MHC I-presented peptidome at the surface of other nucleated cells to kill transformed or infected ones and limit disease spreading. MHC II-restricted antigens are mostly of extracellular origin (Fig. 1, blue arrows). Extracellular antigens are captured by receptor mediated endocytosis, phagocytosis or macropinocytosis. Phagosome and endosome content gets digested during their progression towards MHC II-containing late endosomal compartments (MIIC), which display the biochemical features of multivesicular bodies (MVB) (Schmid et al., 2007). Newly synthetized MHC II complexes, with their antigen-binding groove shielded by the invariant chain chaperone (Ii), are also addressed to MIIC. There, Ii is degraded by specialized endosomal proteases, such as cathepsin S (Bania et al., 2003), and the remaining Ii peptide (CLIP), still occupying the groove, is exchanged by the HLA-DM dimers for peptides derived from internalized antigens (Blum et al., 2013). Peptide-loaded MHC II are then transported to the plasma membrane through a complex recycling pathway involving ubiquitination and members of the MARCH E3-ligases family (De Gassart et al., 2008; Shin et al., 2006; van Niel et al., 2006). In DCs, activation by microbial products or inflammatory cytokines alters traffic of MHC II and co-stimulatory molecules, enhancing CD4 + T cell (T helper) stimulatory capacity of the DCs. Although the specificity of MHC I and MHC II is well known, restrictions are not absolutely tight and extracellular antigens can be presented by MHC I in a process known as cross-presentation (Amigorena and Savina, 2010), while MHC II can be associated with endogenous antigens. Cross-presentation (CP) allows cells such as DCs to prime CTLs without the need for being infected or transformed to display pathogen- or tumour-derived antigens (Cruz et al., 2017). CP occurs notably in the XCR1+ DC subtype and is favoured by microbial or type-I interferon-dependent activation (Vu Manh et al., 2015). To deliver antigens to MHC I, two main pathways have been implicated (Fig. 1, yellow arrows). The cytosolic pathway, in which phagocytosed proteins are transported to the cytoplasm through an ill-defined molecular mechanism, enabling proteasome-mediated processing into peptides, which are translocated to the ER and loaded on MHC I (Kovacsovics-Bankowski and Rock, 1995). Alternatively, the vacuolar pathway allows direct loading of antigenic peptides from lysosomes on MHC I in specific endosomal compartments involving recycling endosomes (Di Pucchio et al., 2008).