Apprêtement des antigènes présentés par les molécules de classe I du CMH

Les défenses immunitaires de l’organisme vis-à-vis des agents pathogènes et des cellules malignes reposent en grande partie sur la surveillance par les lymphocytes T cytotoxiques. Cette surveillance est rendue possible par un système d’apprêtement (processing) des protéines cellulaires, qui fournit des échantillons peptidiques aux molécules de classe I exprimées à la surface cellulaire. Pour produire en permanence une gamme de peptides représentative du monde des protéines fabriquées par la cellule, de façon fidèle et quasiment en temps réel, ce système exploite des voies fondamentales du métabolisme cellulaire, auquel il associe certains acteurs ayant une fonction plus spécialisée. Ainsi, un élément clef du métabolisme des protéines cellulaires, le protéasome, principale protéase du cytosol, est exploitée comme source de peptides, en prélevant une petite fraction de peptides pour la surveillance immunitaire. Ce sont les différentes étapes requises pour associer ces peptides aux molécules de classe I du CMH (complexe majeur d’histocompatibilité) qui sont discutées dans cet article.The immune defences of our organism against pathogens and malignant transformation rely to a large extent on surveillance by cytotoxic T lymphocytes. This surveillance in turn depends on the antigen processing system, which provides peptide samples of the cellular protein composition to MHC (major histocompatibility complex) class I molecules displayed on the cell surface. To continuously and almost in real time provide a representative sample of the array of proteins synthesized by the cell, this system exploits some fundamental pathways of the cellular metabolism, with the help of several dedicated players acting exclusively in antigen processing. Thus, a key element in the turnover of cellular proteins, protein degradation by cytosolic proteasome complexes, is exploited as source of peptides, by recruiting a minor fraction of the produced peptides as ligands for MHC class I molecules. These peptides can be further processed and adapted to the precise binding requirements of allelic MHC class I molecules by enzymes in the cytosol and endoplasmic reticulum. The latter compartment is equipped with several dedicated players helping peptide assembly with class I molecules. These include the TAP (transporter associated with antigen processing) membrane transporter pumping peptides into the ER, and tapasin, a chaperone with a structure similar to MHC molecules that tethers class I molecules awaiting peptide loading to the TAP transporter, and mediates optimization of MHC class I ligand by a still somewhat mysterious mechanism. Additional “house-keeping” chaperones that are known to act in concert in ER quality control, assist and control correct folding, oxidation and assembly of MHC class I molecules. While this processing system handles exclusively endogenous cellular proteins in most cells, dendritic cells employ one or several special pathways to shuttle exogenous, internalized proteins into the system, in a process referred to as cross-presentation. Deciphering the cell biological mechanism creating the link between the endosomal and secretory pathways that enables cross-presentation is one of the challenges faced by contemporary research in the field of MHC class I antigen processing

Endocytic Recycling of MHC Class I Molecules in Non-professional Antigen Presenting and Dendritic Cells

Major histocompatibility complex class I (MHC I) molecules are glycoproteins that display peptide epitopes at the cell surface of nucleated cells for recognition by CD8+ T cells. Like other cell surface receptors, MHC class I molecules are continuously removed from the surface followed by intracellular degradation or recycling to the cell surface, in a process likely involving active quality control the mechanism of which remains unknown. The molecular players and pathways involved in internalization and recycling have previously been studied in model cell lines such as HeLa. However, dendritic cells (DCs), which rely on a specialized endocytic machinery that confers them the unique ability to “cross”-present antigens acquired by internalization, may use distinct MHC I recycling pathways and quality control mechanisms. By providing MHC I molecules cross-presenting antigens, these pathways may play an important role in one of the key functions of DCs, priming of T cell responses against pathogens and tumors. In this review, we will focus on endocytic recycling of MHC I molecules in various experimental conditions and cell types. We discuss the organization of the recycling pathway in model cell lines compared to DCs, highlighting the differences in the recycling rates and pathways of MHC I molecules between various cell types, and their putative functional consequences. Reviewing the literature, we find that conclusive evidence for significant recycling of MHC I molecules in primary DCs has yet to be demonstrated. We conclude that endocytic trafficking of MHC class I in DCs remains poorly understood and should be further studied because of its likely role in antigen cross-presentation

Investigating the relationship between actual smartphone use and delay discounting

The omnipresence of smartphones among adolescents and adults gives rise to the questions about excessive use and personality factors which are associated with heavier engagement with these devices. Previous studies have found behavioral similarities between smartphone use and maladaptive behaviors (e.g. drinking, gambling, drug abuse) in the context of intertemporal choice but mostly relied on participants’ self-reports regarding engagement with their phone. In this study, we collected actual usage data by smartphone application from 101 participants and assessed their tendency to discount future rewards, their reward responsiveness, self-control and consideration of future consequences. We found that smartphone screen time was correlated with choosing smaller immediate over larger delayed rewards and that usage of social media and gaming apps predicted delay discounting. Additionally, smartphone use was negatively correlated with self-control but not correlated with consideration of future consequences. Neither psychological variable could mediate the relationship between smartphone usage and delay discounting. Our findings provide further evidence that smartphone use and impulsive decision-making go hand in hand and that engagement with these devices needs to be critically examined by researchers to guide prudent behavior

Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets

Recognition of pancreatic beta cell antigens by autoreactive T lymphocytes plays a central role in the pathogenesis of insulin-dependent type 1 diabetes. Recent results suggest that non-conventional antigenic epitope processing and presentation may contribute to triggering and maintaining autoreactive responses. Moreover, promising results raise hope that autoantigens may become safe and specific therapeutics for type 1 diabetes in the future

Delay Discounting of Monetary and Social Media Rewards: Magnitude and Trait Effects

Humans discount rewards as a function of the delay to their receipt. This tendency is referred to as delay discounting and has been extensively researched in the last decades. The magnitude effect (i.e., smaller rewards are discounted more steeply than larger rewards) and the trait effect (i.e., delay discounting of one reward type is predictive of delay discounting of other reward types) are two phenomena which have been consistently observed for a variety of reward types. Here, we wanted to investigate if these effects also occur in the context of the novel but widespread reward types of Instagram followers and likes and if delay discounting of these outcomes is related to self-control and Instagram screen time. In a within-subject online experiment, 214 Instagram users chose between smaller, immediate and larger, delayed amounts of hypothetical money, Instagram followers and likes. First, we found that the magnitude effect also applies to Instagram followers and likes. Second, delay discounting of all three reward types was correlated, providing further evidence for a trait influence of delay discounting. Third, no relationships were found between delay discounting and self-control as well as Instagram screen time, respectively. However, a user’s average like count was related to delay discounting of Instagram likes

A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural ligands from HIV envelope protein

Viral antigens complexed with major histocompatibility complex (MHC) class I molecules are recognized by cytotoxic T lymphocytes on infected cells. Assays with synthetic peptides identify optimal MHC class I ligands often used for vaccines. However, when natural peptides are analyzed, more complex mixtures including long peptides bulging in the middle of the binding site or with carboxyl extensions are found, reflecting lack of exposure to carboxypeptidases in the antigen processing pathway. In contrast, precursor peptides are exposed to extensive cytosolic aminopeptidase activity, and fewer than 1% survive, only to be further trimmed in the endoplasmic reticulum. We show here a striking example of a nested set of at least three highly antigenic and similarly abundant natural MHC class I ligands, 15, 10, and 9 amino acids in length, derived from a single human immunodeficiency virus gp160 epitope. Antigen processing, thus, gives rise to a rich pool of possible ligands from which MHC class I molecules can choose. The natural peptide set includes a 15-residue-long peptide with unprecedented 6 N-terminal residues that most likely extend out of the MHC class I binding groove. This 15-mer is the longest natural peptide known recognized by cytotoxic T lymphocytes and is surprisingly protected from aminopeptidase trimming in living cells.This work was supported by grants from European Union, Ministerio de Educación y Ciencia, Comunidad de Madrid, Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Sindrome de Inmunodeficiencia Adquirida (SIDA) del Fondo de Investigaciones Sanitarias (to M. D. V.), Comunidad de Madrid, Instituto de Salud Carlos III, Fundación para la Investigación y la Prevención del Sindrome de Inmunodeficiencia Adquirida en España (to D. L.), and by European Commission Grant QLK2-CT-2001-01167 (to P. M. V. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.S

A Detailed Analysis of the Murine TAP Transporter Substrate Specificity

The transporter associated with antigen processing (TAP) supplies cytosolic peptides into the endoplasmic reticulum for binding to major histocompatibility complex (MHC) class I molecules. Its specificity therefore influences the repertoire of peptides presented by MHC molecules. Compared to human TAP, murine TAP's binding specificity has not been characterized as well, even though murine systems are widely used for basic studies of antigen processing and presentation.We performed a detailed experimental analysis of murine TAP binding specificity by measuring the binding affinities of 323 peptides. Based on this experimental data, a computational model of murine TAP specificity was constructed. The model was compared to previously generated data on human and murine TAP specificities. In addition, the murine TAP specificities for known epitopes and random peptides were predicted and compared to assess the impact of murine TAP selectivity on epitope selection.Comparisons to a previously constructed model of human TAP specificity confirms the well-established differences for peptide substrates with positively charged C-termini. In addition these comparisons show that several residues at the N-terminus of peptides which strongly influence binding to human TAP showed little effect on binding to murine TAP, and that the overall influence of the aminoterminal residues on peptide affinity for murine TAP is much lower than for the human transporter. Murine TAP also partly prefers different hydrophobic amino acids than human TAP in the carboxyterminal position. These species-dependent differences in specificity determined in vitro are shown to correlate with the epitope repertoire recognized in vivo. The quantitative model of binding specificity of murine TAP developed herein should be useful for interpreting epitope mapping and immunogenicity data obtained in humanized mouse models