Apprêtement des antigénes présentés par les molecules de classe I du CMH

Abstract

Les défenses immunitaires de l’organisme vis-àvis des agents pathogènes et pathogens and 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.