Antigen Processing and Presentation

With Professor Peter J. Delves

Saman Awan, [email protected]

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 Learning Objectives

• Describe how T cells recognize protein antigens in the

context of MHC molecules.

• Discover the diversity of the MHC.

• Identify the two main pathways of antigen processing

and presentation.

• Recognize that cross-presentation is also commonly

employed.

• Explain how glycolipid and lipoprotein antigens are

presented to T cells.

Saman Awan, [email protected]

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 Overview

T cells recognize protein antigens that are:

• Processed into peptides

Proteases

• Then presented to the T cell receptor

(TCR) by MHC

Saman Awan, [email protected]

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 The MHC

Major histocompatibility complex

• A complex of genes that are the major determinants of tissue compatibility during
transplantation

• Of course, did not evolve to frustrate attempts at transplantation!

• Used to show protein antigens to T cells

• Human: HLA

• Mouse: H-2

Saman Awan, [email protected]

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 Two Classes of MHC

MHC MHC
class I class II

HLA-A, -B, -C HLA-DP, -DQ, -DR

Present on professional APCs (dendritic cells,

Present on all nucleated cells in the body macrophages, B cells) and on thymic
epithelium

Alerts CD8+ cytotoxic T cells to intracellular Alerts CD4+ helper T cells and regulatory
antigens T cells to extracellular antigens

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 The MHC Gene Locus

Chromosome 6

Class II Class III Class I

DP DQ DR C4 Factor C2 Lympho- TNFα B C A

B toxin

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 Polymorphism of MHC Class I and II Molecules

Peptide binding groove

Non-polymorphic
regions

MHC Class I

Saman Awan, [email protected]

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 Polymorphism of MHC Class I and II Molecules

Peptide binding groove

Polymorphic regions
α-helices
β-sheet floor

MHC Class I

Saman Awan, [email protected]

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 Polymorphism of MHC Class I and II Molecules

Peptide binding groove

Polymorphic regions
α-helices
β-sheet floor

MHC Class I MHC Class II

Saman Awan, [email protected]

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 Polymorphism of MHC Class I and II Molecules

Non-polymorphic
regions

MHC Class I MHC Class II

Saman Awan, [email protected]

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 TCR Recognition of Peptide-MHC (pMHC) Ensures Cell-Cell Contact

MHC class I presents peptides to CD8+ cytotoxic T cells.

CD8

TCR

pMHC I

Infected cell Killing by fas-fasL and/or Cytotoxic T cell

perforin-granzyme pathways
Saman Awan, [email protected]
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 TCR Recognition of Peptide-MHC (pMHC) Ensures Cell-Cell Contact

MHC class II presents peptides to CD4+ helper or regulatory T cells.

CD4

TCR

pMHC II

Helper or
Professional APC regulatory T cell
Release of cytokines

Saman Awan, [email protected]

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 The Diversity of the MHC

DP DQ DR B C A
M 24 91 4 8 17 84
Number of
α- chain >40 >50 7 >4,000 >2,000 >3,000
allelic
β- chain >600 >900 ̴2,000 1 1 1
variants

P 6 69 4 27 46 2
DP DQ DR B C A

Saman Awan, [email protected]

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 MHC Class I Structure
Peptide antigen

α2-domain α1-domain

α-chain

β2-microglobulin
α3-domain

Plasma membrane

Peakman, Mark: Basic and Clinical Immunology. 2nd Edition. Elsevier. 2009. Fig 5.6

Saman Awan, [email protected]

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 MHC Class I Structure

α-helix

β-sheet floor

α-helix

Peakman, Mark: Basic and Clinical Immunology. 2nd Edition. Elsevier. 2009. Fig 5.6

Saman Awan, [email protected]

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 Polymorphic Residues in MHC Class I

α-helix

β-sheet floor

α-helix

Peakman, Mark: Basic and Clinical Immunology. 2nd Edition. Elsevier. 2009. Fig 5.7

Saman Awan, [email protected]

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 MHC Class II Structure
Peptide-binding
groove Peptide

Disulfide bond

lg domain

Abbas, Abul: Cellular and Molecular Immunology. 8th Edition. Elsevier. 2014. Fig 6.10

Saman Awan, [email protected]

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 Peptide Sits in the Peptide-Binding Groove

HLA-A2 (Class I) HLA-DR1 (Class II)

8–9 amino acid peptide ̴ 15 amino acid peptide

Abbas, Abul: Cellular and Molecular Immunology. 8th Edition. Elsevier. 2014. Fig 6.13

Saman Awan, [email protected]

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 Each MHC Variant Can Bind Many Different Peptides

Abbas, Abul: Cellular and Molecular Immunology. 8th Edition. Elsevier. 2014. Fig 6.13

Saman Awan, [email protected]

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 Each MHC Variant Can Bind Many Different Peptides

for example tyrosine or leucine or

phenylalanine isoleucine or
methionine or
valine
Abbas, Abul: Cellular and Molecular Immunology. 8th Edition. Elsevier. 2014. Fig 6.13

Saman Awan, [email protected]

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 Two Main Pathways of Antigen Processing

Endogenous: produces peptides 8-9

amino acids long pMHC I

for presentation by MHC class I

Exogenous: produces peptides

approx 15 amino acids long pMHC II

for presentation by MHC class II

Saman Awan, [email protected]

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 Endogenous Antigen Processing and Presentation

MHC I

TAP1
TAP2 pMHC class I
presented to
ER Immunoproteasome
Tapasin CD8+ T cell
calreticulin Peptides
Erp57 (8/9 amino acids long) Ubiquitination Protein

Saman Awan, [email protected]

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 Exogenous Antigen Processing and Presentation

DM Peptide
MHC II DO exchange

pMHC class II
presented to
ER CD4+ T cell
Invariant Peptides
chain (Ii) ( ̴15 amino
acids long)

Protein Endocytosis/phagocytosis

Saman Awan, [email protected]

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 Cross-Presentation

Cell
• The endogenous and exogenous pathways
are not completely separated.
Endogenous
antigen
• Endogenous antigens can enter the class II
pathway and be presented to CD4+ helper pMHC II
and regulatory T cells.

• Exogenous antigens can enter the class I

pathway and be presented to CD8+
Exogenous
cytotoxic T cells. pMHC I
antigen

Saman Awan, [email protected]

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 Cross-Presentation

Abbas, Abul: Cellular and Molecular Immunology. 8th Edition. Elsevier. 2014. Fig 6.20

Saman Awan, [email protected]

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 Presentation of Lipid Antigens by CD1

CD1

CD1 with lipid

presented to
ER αβ T cell,
γδ T cell,
or NKT cell
Lipases
Glycolipid or Endocytosis/phagocytosis
lipoprotein

Saman Awan, [email protected]

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 Learning Outcomes

 Describe how T cells recognize protein antigens in the

context of MHC molecules.

 Discover the diversity of the MHC.

 Identify the two main pathways of antigen processing and

presentation.

 Recognize that cross-presentation is also commonly

employed.

 Explain how glycolipid and lipoprotein antigens are

presented to T cells.

Saman Awan, [email protected]

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 List of References

Basic and Clinical Cellular and Molecular

Immunology, 2nd Edition Immunology, 8th Edition
Peakman Abbas

Saman Awan, [email protected]

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 This document is a property of: Saman Awan

Note: This document is copyright protected. It may not be copied, reproduced, used, or
distributed in any way without the written authorization of Lecturio GmbH.

Saman Awan, [email protected]

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