Jensen- AP Review

Jensen- AP Review - REVIEW 2007 Nature Publishing Group...

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Recent advances in antigen processing and presentation Peter E Jensen Heterogeneous intracellular pathways and biochemical mechanisms are responsible for generating the glycoprotein complexes of peptide and major histocompatibility complex that are displayed on the surfaces of antigen-presenting cells for recognition by T lymphocytes. These pathways have a profound influence on the specificity of adaptive immunity and tolerance, as well as the context and consequences of antigen recognition by T cells in the thymus and periphery. The field of antigen processing and presentation has continued to advance since the publication of a focus issue on the topic in Nature Immunology in July 2004. Progress has been made on many fronts, including advances in understanding how proteases, accessory molecules and intracellular pathways influence peptide loading and antigen presentation in various cell types. Two generally distinct pathways are used by major histocompatibility complex (MHC) class I and class II molecules for the presentation of peptide antigens to CD8 + and CD4 + T cells, respectively 1–4 . The MHC class I antigen presentation pathway is active in almost all cell types, providing a mechanism for displaying at the cell surface a sample of peptides derived from proteins that are being synthesized in the cell at any given time. Thus, the internal proteome is made available for sur- veillance by cytolytic CD8 + T cells, which have the ability to detect and kill cells expressing viral proteins or tumor antigens. The MHC class II pathway is constitutively active only in ‘professional’ antigen-presenting cells (APCs), including dendritic cells (DCs), B cells, macrophages and thymic epithelial cells. The generation of peptide–MHC class II com- plexes and the expression of costimulatory molecules and cytokines in APCs are highly regulated, reflecting the critical importance of CD4 + T cells in regulating almost all components of adaptive immunity. The peptides presented by MHC class II molecules are derived from proteins that gain access to endosomal compartments, providing a way for CD4 + T cells to respond to exogenous antigens internalized by APCs through phagocytosis, macropinocytosis, receptor-mediated endocytosis and other mechanisms. MHC class I and class II proteins use very similar peptide-binding domain structures to form complexes with peptide antigens 5 ( Fig. 1 ). For both classes, peptides are mostly buried in the peptide-binding groove, and the peptide is an integral part of the properly folded pro- tein. Peptides are held in place by two sets of noncovalent interactions that include sequence-dependent interactions between side chains in the peptide (anchors) and subsites or pockets in the peptide-binding groove and a conserved hydrogen-bond network formed by nonpolymorphic amino acids in MHC proteins and main-chain atoms of bound peptides. The anchor-pocket interactions determine peptide-binding specificity,
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.

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Jensen- AP Review - REVIEW 2007 Nature Publishing Group...

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