Second International Workshop on Antigen Processing and Presentation (Bar Harbor, October 16–18, 1999)

T cells recognize and respond to minute quantities of antigen during host immunological responses to invading pathogens and tumors. To further the challenge, T cells must distinguish these foreign antigens from the more abundant self proteins and macromolecules produced by the host and within which, all cells bathe. Specialized cell surface proteins, major histocompatibility complex (MHC) proteins and CD1 family members, have evolved to display antigens on the surface of select cells in a form which T cells can uniquely recognize. To rationalize how distinct antigens were processed and sorted for presentation, immunologists neatly dissected the cell into two compartments from which antigens could be drawn — the cytoplasm and the endosomal/lysosomal network. Thus, antigens from infectious agents generated in the cytoplasm would be processed there and transported to the ER for complex formation with MHC class I proteins, followed by transit to the cell surface via a default secretory pathway. In contrast, pathogens or antigens entering the endosomal/phagosomal network would be processed and bind MHC class II proteins, with subsequent sorting back to the cell surface. This rigid, compartmentalized model of antigen presentation has given way to a more fluid view with intersecting pathways and cell-specific divergences, as revealed at the 2nd International Conference on Antigen Processing and Presentation at Jackson Laboratories in Bar Harbor, Maine (October 16–18, 1999). Viral and tumor antigens have long been fair game as targets for MHC class I-restricted presentation. Convention holds that these antigens produced in the cytoplasm or en route to the nucleus, are fragmented by the multi-catalytic proteasome yielding peptide ligands for MHC class I molecules. The nature of the substrates acted on by the proteasome remains clouded. Results presented by J. Yewdell suggest that many peptides may be derived from DriPs, Defective Ribosomal Products resulting from failures in complete translation and the folding of full length gene products. A contentious topic at the 1st International Conference on Antigen Processing and Presentation at Oxnard, CA in 1995, was the potential for delivery of exogenous antigens to class I molecules in monocytic cells. S. Amigorena and colleagues from Paris, Utrecht, and Milan, have now proposed a specialized pathway to access class I proteins in dendritic cells with antigen translocation from endosomes to the cytoplasm. Within the cytoplasm, the proteasome still predominates as the key enzyme required for peptide generation, yet tantalizing evidence suggests that other proteases may regulate class I-restricted presentation. Studies of mice with targeted disruptions in the proteasome regulator PA28, revealed alterations in class I-restricted antigen presentation (K. Früh and colleagues, San Diego, CA). Aminopeptidases play a role in trimming peptides within the cytoplasm and the ER as demonstrated by K. Rock (Amherst) and P. van Endert (Paris). A requirement for non-proteasomal processing was also suggested by studies of distinct class I alleles (V. Engelhard, Charlottesville, VA). Elegant studies to fine map the processing of cytoplasmic peptides by the proteasome and other enzymes were offered by T. Serwold and N. Shastri (Berkeley, CA). Contrary to dogma, cytoplasmic antigens may also gain access to endosomal class II molecules by a yet undefined pathway. Cytoplasmic processing was shown to be essential for the presentation of select antigens by class II proteins (J. Lich, Indianapolis, IN) while regulating the display of other antigens (S. Kovats, Duarte, CA). To enhance foreign antigen presentation amid a sea of self molecules, specialized mechanisms have evolved in professional antigen presenting cells for uptake and processing. In B cells, the molecular requirements for receptor-mediated antigen uptake via the BCR and the localization of this receptor in lipid rafts was reported by S. Pierce (Evanston, IL). Potentially important in autoimmunity, presentation of agalactosyl-antigens via dendritic cells was enhanced as a result of receptor-mediated uptake (R. Salter, Pittsburgh, PA). The role of rab proteins in modulating antigen uptake and presentation by B lymphocytes was demonstrated by E. Bertram and T. Watts (Toronto). Antigen uptake and sorting is also modulated in dendritic cells as discussed by W. Garrett and I. Mellman (New Haven, CT). Independent of endosomal pathways, phagosomal antigen processing and localized binding to class II proteins can occur, with the potential for modulation of class II-restricted antigen presentation by microbial products as revealed by C. Harding (Cleveland, OH). Endosomal compartments were also shown to be important in the processing and presentation of lipid antigens rather than peptides via CD1 molecules (M. Brenner, Boston, MA). Dogma has long held that acidic proteases within endosomes and lysosomes are required for processing antigens for the class II pathway. Studies with cathepsin knock-out animals confirmed the importance of these acidic proteases in processing antigens and the invariant chain, a chaperone for class II molecules (T. Nakagawa and A. Rudensky, Seattle, WA and H. Ploegh, Boston, MA). Yet, studies by C. Watts (Dundee) suggest enzymes such as a novel asparagine specific endopeptidase (AEP), play key roles in regulating class II-restricted antigen presentation. The potential for engineering epitopes within an antigen to facilitate processing and class II-restricted presentation was also proposed by S. Schneider and E. Sercarz (San Diego, CA). Reduction of disulfide bonds appears essential for the presentation of some antigens, yet little is known concerning the enzymes which regulate this process in endosomal/lysosomal compartments. Studies on a Gamma interferon-Inducible Lysosomal Thiol (GILT) reductase were presented by U. Phan, M. Maric and P. Cresswell (New Haven, CT). Processing may not always be productive in antigen presentation, as demonstrated by the destruction of some epitopes by surface proteases on dendritic cells (R. Salter, Pittsburgh, PA). The capture of antigenic fragments by MHC molecules represents an entirely different challenge for cells. A carefully orchestrated panel of chaperones have evolved to hold MHC molecules ready for peptides, while allowing exchange or editing to facilitate the selection of the most stable ligands. In the ER, empty class I molecules sequentially bind the chaperones calnexin and calreticulin followed by association with the cytoplasmic to ER peptide transporter, TAP and another accessory molecule tapasin. Studies suggesting some interchange in the functions of calnexin and calreticulin were discussed by D. Williams (Toronto), with the observation that the topological orientation of these proteins may be a key difference. T. Hansen (St Louis, MO) described a novel approach to epitope tag empty class I molecules to monitor chaperone function and peptide loading. Peptide selection by the TAP transporter was also discussed (P. van Endert, Paris), with a model proposed for TAP function based on photobleaching studies (J. Neefjes, Amsterdam). Most intriguing was the view that tapasin may act as a peptide editor to both qualitatively and quantitatively influence class I antigen presentation (J. McCluskey, Victoria). Defects in class I presentation were also observed in tapasin deficient mice (A. Grandea, Nashville, TN). Mutant cell lines lacking TAP and tapasin should also prove informative as suggested by T. Serwold and N. Shastri (Berkeley, CA). In contrast with class I molecules, MHC class II proteins transit with a protective chaperone, the invariant chain to endosomal compartments where proteolytic release of invariant chain occurs and antigenic peptides bind. Mutational analysis of the class II peptide binding groove, along with ligand dissociation studies suggest that hydrogen bonding is important in stable peptide binding (A. Sant, Chicago, IL), shaping of the peptide binding groove into a peptide receptive form (S. Sadegh-Nasseri, Baltimore, MD), and the exchange of peptide ligands (J. Kappler, Denver, CO). These studies of peptide destablization, may also provide insights into the mechanism of action of DM, which serves as an editor for class II molecules to promote unstable peptide exchange. Mutational analysis of DR identified the face involved in DM interaction, and mutational analysis of DM is underway (B. Mellins, Palo Alto, CA). Crystallographic analysis of murine DM alleles is underway as discussed by C. Nelson and D. Fremont (St Louis, MO). Work by A. Vogt (Heidelberg) suggests both positive and negative regulation of DM function by another MHC-encoded protein, DO. While DM is predominantly found in endosomal/lysosomal compartments, the suggestion was offered that a subpopulation of DM expressed on the surface of B cells and immature dendrtitic cells bound to putatively empty class II molecules, thereby facilitating peptide loading and editing (H. Kropshofer, Heidelberg). Perhaps even more intriguing, L. Stern (Boston, MA) reported on the identification of empty class II proteins on the surface of dendritic cells which may readily bind peptides, a finding with relevance to the use of dendritic cells as vaccine reagents for tumor immunotherapy. Multiple pathways may deliver peptide loaded MHC class II molecules to the cell surface while shielding these complexes from digestion in lysosomes (M. Kleijmeer, Utrecht). Most interesting may prove to be the specialized pathways for MHC class II complex export which have evolved in dendritic cells (M. Kleijmeer and colleagues, Utrecht; S. Turley and I. Mellman, New Haven, CT). Overall, this 2nd International Conference on Antigen Processing and Presentation demonstrated that great progress has been made in understanding the molecular events which guide peptide association with MHC molecules. Still, mysteries abound in terms of antigen sorting, the regulation of antigen processing, and quality control or editing reactions that guide peptide presentation by MHC proteins in cells. Perhaps the next great vista for those brave at heart, the processing and selection of lipid antigens for presentation by CD1 molecules, will unfold at the future meetings of this group of immunologists and cell biologists. J. Lich was supported by an NIH predoctoral fellowship award T32-DK07519.

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