Making Peptides for PresentationA Pictorial Introduction

SAMSI3 March 2005

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)

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)

MHC Ribbons

MHC-peptide : T Cell Ribbons

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

Determinant capture Competitive capture

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

CD1● Function

– Present lipids● Group 1

– CD1a, CD1b, CD1c, CD1e– Recognised by conventional T cells– mainly microbial lipids

● Group 2– CD1d– Recognised by Natural Killer T cells– mainly self lipids

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?

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)