Febuxostat australia Although CP has been an important resea

Although CP has been an important research subject in the field of antigen processing and presentation, the mechanisms of presentation of intracellular Febuxostat australia by MHC II received considerably less attention. Interestingly, pioneering work by the Münz laboratory has pointed to an involvement of autophagy in this process (Fig. 1, violet arrows), raising numerous questions on the impact of autophagy regulation on different aspects of endogenous antigen processing and MHC II-restricted presentation by APCs (Argüello et al., 2016; Münz, 2016a, 2016b, 2015).
Autophagy and antigen presentation Macroautophagy (hereafter referred to as autophagy) is a physiological phenomenon that allows cells to degrade and recycle different cytoplasmic components. Numerous review articles have recently described the detailed molecular mechanism regulating autophagy (e.g.Dikic and Elazar, 2018) and we provide here only a brief summary of these findings. The mTOR Complex 1 (mTORC1) is a nutrient/energy/redox sensor and controller of protein synthesis. that upon inactivation (e.g. upon starvation) induces autophagy by stimulation of the autophagy initiator complex kinases ULK1/2 (Mizushima, 2010). Activated ULK recruits phophatidylinositol-3 kinase Vps34 complex to the endoplasmic reticulum (ER) and activates it to produce phosphatidylinositol-3-phosphate (PI3P) in the pre-autophagosomal membrane (Dooley et al., 2014). Subsequently, PI3P effectors mediate lipidation of the Atg8-family members (e.g. LC3, GABARAP), that promotes autophagosome formation upon sequestration of cytoplasmic content by an engulfing double-membrane. Autophagosomes then fuse with lysosomes in a tightly regulated biochemical process, and all their content, including the inner autophagosomal membrane, is digested by lysosomal enzymes. In APCs, autophagosome fusion with MIIC allows access of cytosolic antigens to the MHC II loading machinery (Fig. 1, violet arrows). This autophagy-mediated antigen processing and presentation pathway allows stimulation of CD4+ T cells specific for intracellular antigens. This process is particularly important for negative T cell selection in the thymus (Nedjic et al., 2008), as well as for induction of an efficient anti-viral immune response (Münz, 2016a). Autophagy-dependent antigen presentation may also be relevant during autoimmunity. Expression of the autophagy related protein Atg5 by DCs is required for the presentation of myelin antigen that promotes experimental immune encephalomyelitis (EAE) in the murine model of multiple sclerosis (Keller et al., 2017). Thus, autophagy-mediated antigen presentation is clearly an immunologically relevant process, which, has not yet been semantically defined. To facilitate its description, we propose the term “Type 2 cross-presentation” (CP2), to define the molecular activities leading to all types of autophagy-dependent MHC II-restricted presentation of intracellular antigens by APCs. In contrast, traditional MHC I-restricted cross-presentation of extracellular antigens should be termed “Type 1 cross-presentation” (CP1). The numbering also conveniently matches the MHC class used in the respective processes and the chronology of their discovery.
Other roles of autophagy and its associated machinery in antigen presentation In addition to autophagy itself, its molecular machinery facilitates extracellular protein internalization and access to the standard MHC II pathway, through LC3-associated phagocytosis (LAP; Fig. 1, red arrows) (Sanjuan et al., 2007). The use of a common machinery between autophagy and LAP renders the precise dissection of the immunological contribution of CP2 in autophagy-deficient transgenic animals rather difficult (Münz, 2015). In the LAP pathway, LC3B is coupled to the cytosolic side of phagosomal membranes after reactive oxygen species (ROS) production by the microbicidal NADPH oxidase 2 (NOX2), which, depending on the cell type, seems to accelerate or attenuate fusion with lysosomes. When fusion with lysosome is delayed, MHC II presentation of the endocytosed antigens seems to be prolonged, similarly to what has been observed during CP1 (Amigorena and Savina, 2010; Romao et al., 2013).