Antigen presentation by B lymphocytes: how receptor signaling directs membrane trafficking Fulvia Vascotto, Delphine Le Roux, Danielle Lankar, Gabrielle Faure-Andre ´, Pablo Vargas, Pierre Guermonprez and Ana-Maria Lennon-Dume ´ nil Antigen capture and presentation onto MHC class II molecules by B lymphocytes is mediated by their surface antigen receptor — the B-cell receptor (BCR). The BCR must therefore coordinate the transport of MHC class II- and antigen- containing vesicles for them to converge and ensure efficient processing. Recently, progress has been made in understanding which and how these vesicular transport events are molecularly linked to BCR signaling. In particular, recent studies have emphasized the key roles of membrane microdomains and the actin cytoskeleton in regulation of membrane trafficking upon BCR engagement. Addresses Unite ´ Inserm 653, Institut Curie, 12 rue Lhomond, 75005, Paris, France Corresponding author: Lennon-Dume ´ nil, Ana-Maria (amlennon@curie.fr) Current Opinion in Immunology 2007, 19:93–98 This review comes from a themed issue on Antigen processing and recognition Edited by Jose ´ Villadangos and Peter van Endert Available online 30th November 2006 0952-7915/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2006.11.011 Introduction Mature resting B lymphocytes capture antigen (Ag) via their specific B-cell receptor (BCR), which comprises a membrane immunoglobulin (mIg) coupled to a signaling module formed by the Iga–Igb dimer [1]. In addition to Ag internalization, BCR stimulation triggers a complex cas- cade of signaling events that ultimately leads to the activation of B lymphocytes, which can then initiate the development of germinal centres (GCs) for production of high affinity antibodies. To complete GC formation, acti- vated lymphocytes must process and present internalized Ag on MHC class II molecules to primed CD4 T cells — a process referred to as T cell–B cell cooperation [2]. Most of the recent efforts to unravel the cellular and molecular events that control Ag capture and processing for presentation by MHC class II molecules in primary antigen-presenting cells (APCs) have focused on dendri- tic cells (DCs). However, recent studies performed on mouse B lymphocytes have demonstrated cell biological properties, in particular concerning the organization of their endocytic route and cytoskeleton network, which make them attractive and helpful models to identify the molecular players that regulate Ag processing. In this review, we will present experimental evidence that sup- ports this statement and will discuss the questions that it raises with respect to the emerging idea that Ag-induced interactions between endocytic vesicles and the cytoske- leton play a key role in regulation of the membrane trafficking events required for MHC class II-restricted Ag presentation. Endocytic trafficking in BCR-stimulated lymphocytes Membrane trafficking events required for Ag processing Shortly after synthesis in the endoplasmic reticulum (ER), MHC class II molecules combine with a type II transmembrane protein — the invariant chain (Ii) — which prevents their premature association with endo- genous peptides. In addition, in its cytoplasmic tail, Ii contains the targeting signals that deliver MHC class II molecules into endocytic compartments for them to be loaded with antigenic peptides (reviewed in [3]). Such peptides are derived from the degradation of internalized Ag by endocytic proteases, which must also cleave Ii to free MHC II molecules for loading — a reaction catalyzed by the chaperone molecule H2-DM (reviewed in [4,5]). In B lymphocytes, the cysteine protease cathepsin S (CatS) performs the last key step of Ii proteolysis, which removes the endosomal retention motif in the cytosolic tail of Ii, thereby allowing MHC class II molecules to be exported to the cell surface [6,7]. Successful Ag proces- sing therefore relies on the following directional mem- brane trafficking events: Ag internalization and targeting into endocytic compartments; MHC class II–Ii com- plexes, proteases and H2-DM convergence towards this incoming pool of Ag; and export of MHC class II–peptide complexes to the cell surface (Figure 1). The precise molecular intersections between these specialized mole- cules and the house-keeping machinery that directs these membrane trafficking events remain largely unknown. Dependence of membrane trafficking and Ag processing on BCR signaling An essential function of the BCR is to ensure that these key events of protein trafficking take place [8]. BCR engagement strongly modifies the endocytic capacity of B lymphocytes: whereas resting mature B cells perform minimal endocytosis, they efficiently uptake Ag when www.sciencedirect.com Current Opinion in Immunology 2007, 19:93–98