Differential use of autophagy by primary dendritic cells specialized in cross-presentation

Abstract

Abbreviations: 3-MA, 3-methyladenine; Atg7-DC CKO, Atg7 DC conditional knockout; BafA, bafilomycin A 1 ; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DALIS, dendritic cell aggresome-like inducible structures; green fluorescent protein, GFP; IFC imaging flow cytometry; LAP, LC3 associated phagocytosis; LC3B, microtubule-associated protein 1 light chain 3 b; MHC II, major histocompatibility complex class II; MHC I, major histocompatibility complex class I; OVA, ovalbumin; OT-I, OVA-specific CD8 C T cell; OT-II, OVA-specific CD4 C T cell; SIM, structured illumination microscopy.Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed "cross-presentation." The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

“…Autophagosomes are implicated in cross-presentation (20). On the basis of the data presented in this article, we propose that they are also engaged in the protection of MOG peptide against destructive processing.…”

“…Regarding the relevance of autophagy for cross-presentation by DCs (20), the capacity of the autoantigen to associate with autophagosomes may be a rate-limiting step. The microtubule-associated LC3, and, in particular, the phosphatidylethanolamine-linked isoform LC3-II, is an accepted phagophore/autophagosome marker.…”

“…Regarding the second issue, we report that, during the processing in primary B cells, the MOG40-48 epitope is destroyed by the endolysosomal protease cathepsin G (CatG). Of special interest concerning the second issue is the observation that LCV infection induces expression of the autophagosome marker L chain 3 (LC3)-II, suggesting activation of the autophagy pathway, which was implicated in Ag cross-presentation (20 In summary, we propose that LCV infection of B cells converts destructive processing of MOG, which is a tolerogenic mechanism (22), into productive processing enabling cross-presentation of the pathogenic MOG40-48 epitope to autoaggressive CTLs. We propose this paradigm as a mechanistic explanation contributing to the wellestablished, but poorly understood, association between EBV and MS.…”

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules

“…amino acid starvation) (145) or where antigens are targeted to autophagosomes (146). Atg7-deficient DCs show defective XPT of soluble but not cell-associated or DEC205-targeted antigen (147). In these settings, it is unclear how autophagy or its components are contributing to XPT.…”

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

“…This second pathway can be activated from outside of the cell by proapoptotic ligands of TNF protein superfamily, like, e.g. Fas ligand (FasL) and TRAIL [2,93]. The ligands bind to proapoptotic receptors on the surface of tarnet (cancer) cells and transmit signal for activation of procaspase-8, and this activates subsequent caspases responsible for the course of apoptosis.…”