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Making Peptides for Presentation A Pictorial Introduction

SAMSI 3 March 2005. Making Peptides for Presentation A Pictorial Introduction. Antigen Presentation. Antigen peptide (MHC Class I and MHC Class II) lipids (CD1) zwitterionic polysaccharides (MHC Class II) Peptide processing endogenous (Class I) exogenous (Class II)

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Making Peptides for Presentation A Pictorial Introduction

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  1. SAMSI 3 March 2005 Making Peptides for PresentationA Pictorial Introduction

  2. Antigen Presentation • Antigen • peptide (MHC Class I and MHC Class II) • lipids (CD1) • zwitterionic polysaccharides (MHC Class II) • Peptide processing • endogenous (Class I) • exogenous (Class II) • cross-presentation (exogenous peptides via Class I)

  3. MHC Class I • Function • Presents cytoplasmic peptides to CD8 T cells • Viral & intracellular pathogens • Machinery • Proteasome • Peptide loading complex • Peptidases • cytosol • ER • Prefers 9-mers (closed ends)

  4. MHC Ribbons MHC-peptide : T Cell Ribbons

  5. MHC Class II • Function • Presents endocytosed peptides to CD4 cells • Extracellular pathogens • Antigen presenting cells only • Machinery • Endosomes/lysosomes, extracellular(!) • Invariant chain • DM and DO • Endosomal proteases • Invariant chain (Ii) processing • Peptide cleavage • Bind and trim • Prefers … • eluted 13- to 22-mers (mode 17- to 19- mers) • can bind up to 51-mers with immunogenicity! • BUT core pockets fit a 9-mer, just like MHC Class I

  6. Determinant capture Competitive capture

  7. Cross-Presentation • Loading of “exogenous” ligands onto MHC Class I on APCs • Essential for priming naïve CD8 T cells • Vaccines targeting CD8 T cell responses • Pathways: • particulate antigens • soluble antigens • direct inter-cellular transfer

  8. CD1 • Function • Present lipids • Group 1 • CD1a, CD1b, CD1c, CD1e • Recognised by conventional ab T cells • mainly microbial lipids • Group 2 • CD1d • Recognised by Natural Killer T cells • mainly self lipids

  9. Speculations for vaccine design • MHC Class I • DRiPs -> DNA vaccines which are designed to misfold (e.g. with kDel) • ERAP processing – proline in position 3 stops processing • MHC Class II • multiple epitope vaccines –> spread out in space or time to minimize determinant capture conflicts • consider 3D structure -> pro-determinants • CD1 • are lipids worth considering for vaccines?

  10. References • Immunology • http://www.nature.com/ni/focus/peptides/index.html • Proteasome modeling • A mathematical model of protein degradation by the proteasome (2005, Biophys J preprint, Rob de Boer) • MAPPP: MHC class I antigenic peptide processing prediction (2003, Appl Bioinform, Mollenkopf) • TAP modeling • Transporter associated with antigen processing preselection of peptides binding to the MHC: a bioinformatic evaluation (2004, J Immunol, Flower)

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