Abstract
Dendritic cells (DCs) present exogenous protein-derived peptides on major histocompatibility complex class I molecules to prime naïve CD8+ T cells. This DC specific ability, called cross-presentation (CP), is important for the activation of cell-mediated immunity and the induction of self-tolerance. Recent research revealed that endoplasmic reticulum-associated degradation (ERAD), which was first identified as a part of the unfolded protein response—a quality control system in the ER—plays a pivotal role in the processing of exogenous proteins in CP. Moreover, DCs express a variety of immuno-modulatory molecules and cytokines to regulate T cell activation in response to the environment. Although both CP and immuno-modulation are indispensable, contrasting ER conditions are required for their correct activity. Since ERAD substrates are unfolded proteins, their accumulation may result in ER stress, impaired cell homeostasis, and eventually apoptosis. In contrast, activation of the unfolded protein response should be inhibited for DCs to express immuno-modulatory molecules and cytokines. Here, we review recent advances on antigen CP, focusing on intracellular transport routes for exogenous antigens and distinctive subcellular compartments involved in ERAD.
Highlights
Dendritic cells (DCs) are a diverse group of specialized leukocytes that promote immunity or tolerance by sampling antigens and presenting them to T cells [1]
DCs are divided into three main populations: Conventional or classical DCs, which are further divided into two subpopulations called T helper 1 (TH1) activating cDCs and T helper 2 (TH2) activating cDCs, plasmacytoid DCs, and monocyte-derived DCs [24,25]
The resultant X-box binding protein 1 (XBP1) spliced isoform (XBP1s), acts as a transcription factor and induces the transcription of three groups of molecules to attenuate endoplasmic reticulum (ER) stress: (i) ER-resident molecular chaperones, which accelerate the folding of de novo proteins, (ii) ER-associated degradation (ERAD)-related molecules, which are responsible for removing unfolded proteins from the ER [66,70,71,72], (iii) molecules involved in lipid synthesis, which are important for ER membrane expansion [73] (Figure 1c)
Summary
Dendritic cells (DCs) are a diverse group of specialized leukocytes that promote immunity or tolerance by sampling antigens and presenting them to T cells [1]. Thereafter, DCs migrate towards the draining lymph nodes, where they process the internalized exogenous proteins and present the antigenic peptides, on major histocompatibility complex class I (MHC I) molecules, to naïve CD8+ T cells [2]. In addition to the classical ERAD substrates (i.e., misfolded and/or unassembled proteins), the accumulation of internalized exogenous proteins in DCs trigger the ERAD pathway and induce the UPR. In addition to antigen presentation, DCs detect various environmental signals using pattern recognition receptors (PRRs) and induce T cells to mount an appropriate immune response based on the surrounding conditions, by exchanging immuno-modulatory molecules on the cell-surface and by releasing specific cytokines [18]. The triggering of innate immunity activated the UPR [21] and an excess of ER stress impaired the immuno-regulatory functions of DCs [22]. We review the current concepts linking CP with the UPR and discuss how the fine tuning of such events allows DCs to perform ER homeostasis and immuno-regulatory functions together
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