Distinct Subcellular Compartments of Dendritic Cells Used for Cross-Presentation

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.

Exosome-Mediated mRNA Delivery For SARS-CoV-2 Vaccination

“…These results raise the possibility that the LSNME/S W1 induces the kind of Th1-skewed cellular response desired for vaccine-induced immunity. These results are consistent with the design of the LSNME open reading frame, which is engineered to drive antigen processing by the MHC Class I and Class II pathways (Gupta et al, 2006; Imai et al, 2019; Wu et al, 1995). Vaccinated animals also developed durable antibody responses to the N and the S proteins.…”

“…The first of these mRNAs encoded a membrane protein (LSNME) comprised of the receptor binding domain (RBD) of S, the entire N protein, and soluble portions of the M and E proteins, all expressed within the extracellular domain of the human Lamp1 protein. This protein is predicted to be degraded into peptides for antigen presentation by the MHC Class I system, and if expressed in antigen-presenting cells (APCs), to be degraded into peptides for antigen presentation by MHC Class II molecules (Gupta et al, 2006)(Imai et al, 2019). Expression of such a protein in a non-APC cell type such as HEK293 is expected to result in its accumulation in the ER, and consistent with this hypothesis, staining HEK293 cells transfected with this mRNA expressed with a COVID- 19 patient plasma identified an ER-localized protein ( Fig.…”

“…As for the modes of S antigen delivery, most enlist host cells to express the S antigen component of their vaccine, from either injected mRNAs (Jackson et al, 2020; Walsh et al, 2020) or infectious viral vectors (Bos et al, 2020; Graham et al, 2020; Hassan et al, 2020; Zhu et al, 2020) while some involve direct injection of purified, recombinant S protein (Keech et al, 2020). Here we describe an alternative approach to SARS-CoV-2 vaccination that combines the features of exosome-based mRNA delivery with the expression of viral antigens in forms designed for antigen presentation by major histocompatibility (MHC) Class I and Class II pathways(Imai et al, 2019). Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that are made by all cells, abundant in all biofluids, and mediate intercellular transmission of signals and macromolecules, including genetic information such as RNAs (Pegtel and Gould, 2019).…”

Phytoglycogen Nanoparticle Delivery System for Inorganic Selenium Reduces Cytotoxicity without Impairing Selenium Bioavailability

“…To this end, inorganic selenium encapsulated into chitosan nanoparticles have demonstrated lower cytotoxic effects, while maintaining selenium's antioxidant properties. 25,26 In the present study, phytoglycogen nanoparticles (PhG NPs), a naturally occurring nanoparticle derived from sweet corn (commercialized as NanoDendrix TM by Glysantis TM , Guelph, ON, Canada) was used to deliver inorganic selenium (either sodium selenite (Na Sel) or selenium dioxide) using two forms of chemistry, namely, ionic and covalent bonding. 27 Notably, the hydrodynamic diameter of the selenium-conjugated nanoparticles (SeNPs), 53-68 nm, is comparable to most nano-selenium produced by chemical technology.…”

Role of Dendritic Cells in Inflammation

“…DCs’ maturation is crucial for antigen presentation and cross-presentation of exogenous peptides on major histocompatibility complex class I molecules to prime naïve CD8 + T cells response. The review by Dr. Imai presents recent advances in the understanding of the intracellular transport routes for correct antigen cross-presentation [ 7 ].…”