Antigen processing and recognition Editorial overview Peter van Endert and Jose ´ A Villadangos Current Opinion in Immunology 2007, 19:63–65 Available online 6th December 2006 0952-7915/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coi.2006.11.015 Peter van Endert INSERM U580, Universite ´ Rene ´ Descartes Paris V, 161 rue de Se ` vres, 75015 Paris, France Email: vanendert@necker.fr Peter van Endert studies MHC class I antigen processing and its role in insulin- dependent diabetes. He has been interested in study of the specificity and function of the TAP peptide transporters, and more recently in peptide trimming by aminopeptidases in the endoplasmic reticulum. Proteolytic enzymes involved in MHC class I antigen processing are a major current topic studied in his laboratory, with emphasis on enzymes that have a specific involvement in cross- presentation and others involved in proteasome-independent antigen degradation. His laboratory is also attempting to translate understanding of antigen processing into rational vaccine components. Jose ´ A Villadangos Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia Email: villadangos@wehi.edu.au Jose ´ Villadangos is interested in the mechanisms involved in processing and presentation of exogenous antigens by way of the MHC class II and MHC class I (cross-presentation) pathways. The antigen-presenting cells that currently occupy most of his attention are the dendritic cells. He is trying to characterize the control checkpoints that regulate antigen presentation in these cells, and to understand the basis for the functional heterogeneity of the dendritic cell network in vivo. He hopes that the information gained with his studies will help to develop better vaccines, efficient dendritic cell- based immunotherapies, and strategies to overcome the immunosuppressive effects of systemic infections. Understanding the mechanisms and rules that govern production of pep- tides presented by MHC molecules remains a fascinating intellectual challenge at the intersection of immunology, cell biology and biochemistry. This issue of Current Opinion in Immunology contains a series of reviews documenting that the field is as vibrant as ever, and might still hold some major surprises that will have an impact beyond the specialist. Some of the reviews we solicited point out tremendous gaps in our knowledge concern- ing crucial molecular pathways such as MHC class I cross-presentation (Monu and Trombetta, Watts et al.), and the origin of MHC class I ligands (Yewdell) as well as that of endogenous MHC class II ligands (Strawbridge and Blum). Other reviews discuss important open questions in better- defined pathways, such as MHC class II presentation by B cells (Len- non-Dume ´ nil and co-workers) and the molecular workings of MHC class I loading complexes (Garbi et al.). As a reminder of the ultimate purpose of our efforts — rational vaccine design — Sette and Peters conclude by outlining the practical challenges that we face when selecting epitopes, produced by antigen processing in an outbred population, as vaccine components. The question of what proteins MHC class I ligands are derived from is an excellent example of how seemingly settled issues can require a compre- hensive re-examination. Following the discovery that the proteasome is involved in generation of most if not all MHC class I peptide ligands [1], it seemed evident that ligand generation was a by-product of cellular protein turnover (i.e. coupled to protein half-life). However, as reviewed by Yew- dell, whose laboratory has driven many of these discoveries, evidence has been accumulating in recent years that many class I ligands are derived from rapidly degraded, presumably defective ribosomal products (DRiPs). A corollary of this notion is that antigenic peptide generation is linked to the rate of translation of a protein rather than to its half-life. However, we are some way from understanding the precise contribution of DRiPs to class I antigen presentation, and how and where they are produced. Yewdell proposes a fascinating working hypothesis to guide the studies to come: the immunoribosome [2]. This hypothetical translation machinery, which might be associated with the endoplasmic reticulum (ER), would specialize in generating conventional and non-conventional translation products for preferential use by the class I processing pathway. Whatever the source of class I ligands, their assembly with MHC molecules requires correct function of MHC class I peptide loading complexes (PLCs). This term refers to an elaborate assembly of empty MHC class I molecules with multiple chaperones, including the oxidoreductase ERp57 and the dedicated ‘peptide editor’ tapasin, which also mediates complex association with the transporters associated with antigen processing [3]. Garbi et al. discuss recent studies of the PLC, focussing on ERp57; knockout of this molecule www.sciencedirect.com Current Opinion in Immunology 2007, 19:63–65