Autophagy promotes MHC class II presentation of peptides from intracellular source proteins

Abstract

MHC-peptide complexes mediate key functions in adaptive immunity. In a classical view, MHC-I molecules present peptides from intracellular source proteins, whereas MHC-II molecules present antigenic peptides from exogenous and membrane proteins. Nevertheless, substantial crosstalk between these two pathways has been observed. We investigated the influence of autophagy on the MHC-II ligandome and demonstrated that peptide presentation is altered considerably upon induction of autophagy. The presentation of peptides from intracellular and lysosomal source proteins was strongly increased on MHC-II in contrast with peptides from membrane and secreted proteins. In addition, autophagy influenced the MHC-II antigen-processing machinery. Our study illustrates a profound influence of autophagy on the class II peptide repertoire and suggests that this finding has implications for the regulation of CD4 ؉ T cell-mediated processes.antigen processing ͉ lysosomal proteases ͉ T helper cells P eptides of foreign and self proteins are presented on MHC-I and MHC-II molecules at the cell surface and can be recognized by CD8ϩ and CD4 ϩ T lymphocytes, respectively (1, 2). From a classical point of view, MHC-I molecules present antigenic peptides derived from intracellular proteins, whereas MHC-II molecules do so for exogenous and membrane proteins (3). This phenomenon is reflected in the two major cellular breakdown pathways for proteins: proteasomal degradation, particularly relevant to the generation of MHC-I peptides (4), and degradation by the endosomal͞lysosomal system, which is responsible for the processing of MHC-II peptides (5). However, the separation of these distinct pools of source proteins is less stringent than originally believed. It is now well established that MHC-I molecules are able to present peptides derived from exogenous antigens (Ag) by a process known as cross presentation (6). On the other hand, intracellular proteins can be presented by MHC-II molecules (7,8), even though the underlying processes are less clear. It has been recently shown that peptides from cytosolic model proteins can be presented on MHC-II molecules through autophagy (9-11). Autophagy plays a role in the endosomal͞lysosomal degradation pathway and is responsible for feeding intracellular components into this pathway. It is thought to be required for normal turnover of cellular components, particularly in response to starvation (12). Against this background, we hypothesized that autophagy might mediate MHC-II presentation of intracellular Ag, meaning the contents of a cell contained within the plasma membrane, excluding large vacuoles and secretory or ingested material (Gene Ontology classifications), in general. Therefore, we performed a detailed characterization of the MHC-II ligand repertoire (ligandome) presented at the cell surface under normal conditions and after increased autophagy, leading to a comprehensive overall picture of changes in peptide processing and presentation. Materials and MethodsCell Culture and Autophagy Inducti...

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Interestingly, composite exposure to TNF‐ α and IFN γ leads to significant autophagy‐dependent translocation of intracellular MHC class II to the cell surface in myocytes and more than 40% of muscle fibers in IBM that costain for autophagosomes and MHC class II have contact to CD4 + and CD8 + infiltrating T cells 108. Dengjel and colleagues reported that upregulation of autophagic activity, by means of altered lysosomal processing, significantly increases the fraction of intracellular source protein‐derived peptides presented on MHC class II 267. These findings suggest that the proinflammatory environment in IBM muscle promotes induction of autophagy in myofibers and subsequently enhances surface MHC class II, thereby maintaining CD4 + T cell infiltrates via the presentation of yet unknown self‐peptides.…”

Cellular senescence: from growth arrest to immunogenic conversion

“…However, it can be speculated that pGE may function to generate an array of tissue-restricted proteins that can subsequently be processed into peptides by autophagic proteases for presentation on MHC molecules (Dengjel et al 2005). Similar to the presentation of tumour-associated antigens (Reuschenbach et al 2009), senescent cells may also present antigens that can be recognized by immune cells, thereby becoming antigen-presenting cells (APCs).…”

L’autophagie et l’homéostasie des lymphocytes T et B

“…Il est en revanche probable qu'elle contribue à l'activation des LB dépendant des LT au cours de la présentation antigénique. L'autophagie favorise en effet la présentation d'antigènes cytosoliques du soi [32] ou d'antigènes viraux intracellulaires par le CMH-II [33]. Si aucune étude n'a montré la pertinence de ces observations in vivo, il apparaît néanmoins possible que l'autophagie, par la présentation antigénique aux LT CD4 + spécifiques d'antigènes intracellulaires, contribue à l'activation de LB autoréactifs ou spéci-fiques d'antigènes viraux.…”