Antigen processing via autophagy--not only for MHC class II presentation anymore?
ABSTRACT T cells monitor intracellular and extracellular protein composition via proteolytic products that are displayed to them on major histocompatibility complex (MHC) molecules. For this purpose it has been documented that MHC class II molecules, which were originally thought to just display lysosomal products of endocytosed proteins to CD4(+) helper T cells, can also present intracellular substrates of autophagic pathways. This has triggered the interest of immunologists into the role of autophagy in antigen processing in general, and recently additional autophagic mechanisms for intracellular and extracellular antigen processing onto MHC class I molecules for presentation to CD8(+) cytolytic T cells have been revealed. Here, I will review the contribution of autophagy for MHC class I and class II antigen processing and presentation to T cells.
Article: Autophagy in protists.[show abstract] [hide abstract]
ABSTRACT: Autophagy is the degradative process by which eukaryotic cells digest their own components using acid hydrolases within the lysosome. Originally thought to function almost exclusively in providing starving cells with nutrients taken from their own cellular constituents, autophagy is in fact involved in numerous cellular events including differentiation, turnover of macromolecules and organelles, and defense against parasitic invaders. During the last 10-20 years, molecular components of the autophagic machinery have been discovered, revealing a complex interactome of proteins and lipids, which, in a concerted way, induce membrane formation to engulf cellular material and target it for lysosomal degradation. Here, our emphasis is autophagy in protists. We discuss experimental and genomic data indicating that the canonical autophagy machinery characterized in animals and fungi appeared prior to the radiation of major eukaryotic lineages. Moreover, we describe how comparative bioinformatics revealed that this canonical machinery has been subject to moderation, outright loss or elaboration on multiple occasions in protist lineages, most probably as a consequence of diverse lifestyle adaptations. We also review experimental studies illustrating how several pathogenic protists either utilize autophagy mechanisms or manipulate host-cell autophagy in order to establish or maintain infection within a host. The essentiality of autophagy for the pathogenicity of many parasites, and the unique features of some of the autophagy-related proteins involved, suggest possible new targets for drug discovery. Further studies of the molecular details of autophagy in protists will undoubtedly enhance our understanding of the diversity and complexity of this cellular phenomenon and the opportunities it offers as a drug target.Autophagy 04/2011; 7(2):127-58. · 7.45 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Autophagy delivers cytoplasmic constituents for lysosomal degradation, and thereby facilitates pathogen degradation and pathogen fragment loading onto MHC molecules for antigen presentation to T cells. Herpesviruses have been used to demonstrate these novel functions of autophagy, which previously has been primarily appreciated for its pro-survival role during starvation. In this review, we summarize recent findings how macroautophagy restricts herpesvirus infections directly, how macroautophagy and chaperone mediated autophagy contribute to herpesviral antigen presentation on MHC molecules, and which mechanisms herpesviruses have developed to interfere with these pathways. These studies suggest that herpesviruses significantly modulate autophagy to escape from its functions in innate and adaptive immunity.Herpesviridae. 01/2011; 2(1):2.
Article: Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion.[show abstract] [hide abstract]
ABSTRACT: Autophagy controls IL-1β secretion by regulating inflammasome activation and by targeting pro-IL-1β for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling; it was abrogated with an IL-1R antagonist or with IL-1-neutralizing Abs, whereas treatment with either rIL-1α or IL-1β induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted enhanced levels of both IL-1β and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-γ, and IL-22 by γδ T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion.The Journal of Immunology 09/2012; 189(8):4144-53. · 5.79 Impact Factor