Making Peptides for Presentation A Pictorial Introduction

1
Making Peptides for PresentationA Pictorial
Introduction

• SAMSI
• 3 March 2005

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
(No Transcript)
6
(No Transcript)
7
(No Transcript)
8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
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

20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
Determinant capture
Competitive capture
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
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

30
(No Transcript)
31
(No Transcript)
32
(No Transcript)
33
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

34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
Speculations for vaccine design

• MHC Class I
• DRiPs -gt 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 gt spread out in space
  or time to minimize determinant capture conflicts
• consider 3D structure -gt pro-determinants
• CD1
• are lipids worth considering for vaccines?

38
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)