Ijnmuno Mhc

REVIEWS

The known unknowns of antigen processing and presentation
Jatin M. Vyas*‡§, Annemarthe G. Van der Veen* and Hidde L. Ploegh*||

Abstract | The principal components of both MHC class I and class II antigen processing and presentation pathways are well known. In dendritic cells, these pathways are tightly regulated by Toll-like-receptor signalling and include features, such ascross-presentation, that are not seen in other cell types. However, the exact mechanisms involved in the subcellular trafficking of antigens remain poorly understood and in some cases are controversial. Recent data suggest that diverse cellular machineries, including autophagy, participate in antigen processing and presentation, although their relative contributions remain to be fully elucidated. Here,we highlight some emerging themes of antigen processing and presentation that we think merit further attention.
Endolysosomal compartments
Endosomes that have fused  with lysosomes. This acidic  environment allows  degradation of antigens. 

*Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. ‡ Department of Medicine, Harvard Medical School, Boston, Massachusetts02115, USA. § Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. || Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. Correspondence to H.L.P. e‑mail: ploegh@wi.mit.edu doi:10.1038/nri2368 Published online 18 July 2008

Since the discovery that T‑cell immunity relies on‘denatured, unfolded, sequential determinants’1 of pro‑ teins, whereas B‑cell (that is, antibody) recognition of the same protein antigen is determined by its tertiary structure, immunologists have been fascinated with anti‑ gen processing and presentation. Decades of work have elucidated the pathways that generate peptide–MHC complexes. As a result, we can now explain most of the fundamental differencesbetween B‑ and T‑cell antigen recognition2,3 and such knowledge is useful for vaccine design and other immune‑based interventions. Recognition of antigens in the peptide‑binding groove of surface‑expressed MHC class I and class II molecules by specific T‑cell receptors is central to T‑cell activation. To fulfil their physiological function, MHC proteins must first acquire peptide antigens, afunction that is executed differently by the two main classes of MHC molecules. For MHC class I molecules, the goal is to report on intracellular events (such as viral infection, the presence of intracellular bacteria or cellular transformation) to CD8+ T cells4. MHC class I molecules are composed of heavy chains and an invari‑ ant light chain, known as β2‑microglobulin. The events of the biosynthesisof MHC class I molecules can be summarized in six steps: one, acquisition of antigenic peptides; two, tagging of the antigenic peptide for destruction by ubiquitylation; three, proteolysis; four, delivery of peptides to the endoplasmic reticulum (ER); five, binding of peptides to MHC class I molecules; and six, display of peptide–MHC class I complexes on the cell surface (FIG. 1). For MHC class IImolecules, the goal is to sample the extracellular milieu and present

antigens to CD4+ T cells4. Similar to MHC class I mole‑ cules, the α‑ and β‑chain of MHC class II molecules are synthesized in the ER and associate with the invari‑ ant chain (Ii; also known as CD74) for proper folding, trafficking and protection of the antigen‑binding groove5. Newly assembled MHC class II molecules are thendelivered by vesicular transport to endolysosomal  compartments that supply peptide antigens. Following peptide loading, peptide–MHC class II complexes are delivered to the cell surface. Despite the involvement of different molecules and cellular compartments, the gen‑ eration of peptide–MHC class II complexes can be strat‑ ified into the same six steps as those for peptide–MHC class I...