• Antigen Presentation to T Lymphocytes (Ch. 6): Major Histocompatibility Complex (MHC)

1.The generation of T-cell receptor ligands• The mechanism of antigen presentation.

2.The major histocompatibility complex and its function• Genetic variability of MHCs

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Major Histocompatibility Complex (MHC)MHC class I MHC class II

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Antigen processing: The modification of an antigen to generate peptides

Antigen presentation: The display of the peptide generated by antigen processing at the cell surface by the MHC.

Antigens: from intracellular or extracellular pathogens

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

1.The mechanism of antigen presentation.

i) MHC class I

ii) MHC class II

APCs: DC, MQ, B cells

MHC Class I pathway

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Transporters Associated with antigen processing (TAP): IFN-γ inducible, prefers peptides of between 8-16 aa.

Proteasome

MHC I

ER

Nucleus

26S ProteasomeImmunoproteasome(increases the cleavage of polypeptide to generate MHC I binding peptides)

20S Core

19S Cap

19S Cap11S (PA28)

11S (PA28):IFN-γ inducibleIncreases the rate at which peptides are released from the proteasome by opening up the gate

Proteasome to Immunoproteasome:

Proteasome

MHC I

ER

Nucleus

TCP-1 ring complex (TRiC): Chaperon to protect peptides

ER Aminopeptidase associated with Antigen Processing (ERAAP)

Proteasome

MHC I

ER

Nucleus

DRiPs: improper splicing, frameshifts, misfolding, etc.

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Viruses produce immunoevasins:

HSV: ICP47 binds TAP

HCMV: US6 inhibits TAP ATPase activity, US11 dislocates MHC 1 in conjuction with derlin

Adenovirus: E19 retains MHC I in ER and prevents the tapasin-TAP interaction to block the peptide loading

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

MHC II:

Acid proteases: Cathepsin B, D, S and L

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Invariant Chain:- trimers associated with MHC II- Protects the peptide binding to MHC II- Deliver the MHC II to a low-pH endosomal compartment- Cathepsin S partially cleaves Ii to Class II-associated

invariant-chain peptide (CLIP)

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The MHC class II-like molecules: HLA-DM (α and β)

- Catalyzes the release of CLIP and the binding of peptides to MHC II- Catalyzes the release of unstably bound peptides from MHC II (peptide editing)- INF-γ inducible

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The MHC class II-like molecules: HLA-DO (α and β)

- Negative regulator of DM

- Binds to HLA-DM and inhibits both the HLA-DM catalyzed release of CLIP from, and the binding of other peptides to MHC II

MHC class II pathway

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MHC I

ER

Nucleus

- Retrograde translocation - to control misfolded proteins

ER-Phagosome fusion

Cross Presentation: Presentation of exogenous antigens by MHC I to CD8 T cells.e.g.. DC engulfing virus infected cells.

Cross-Talk between MHC I and II pathways: 2 to 1

Cross-Talk between MHC I and II pathways: Autophagy (1 to 2)

- Autophagy is the normal process of protein turnover.- Cytosolic proteins and organelles are delivered to lysosomes for degradation.

i) Microautophagy: The cytosol is continuously internalized into the vesicular system by lysosomal invaginations.

ii) Macroautophagy: When starved, a double-membraned autophagosome engulfs cytosol and fuses with lysosomes.

iii) The heat-shock cognate protein 70 (HSC70) and the lysosome-associated membrane protein-2 (LAMP-2) to transport cytosolic proteins to lysosomes.

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2. Genetic variability of MHC.

i) Polygenic: several different MHC class I and II genes

ii) Polymorphic: multiple variants of each gene within the population as a whole

- The MHC is located on chromosome 6 in humans (chromosome 17 in the mouse)- MHC genes are called human leukocyte antigen (HLA) genes- Three MHC I α-chain genes: HLA-A, -B, -C- Three pairs of MHC II α and β –chain genes: HLA-DR, -DP, -DQ (HLA-DR

contains an extra β-chain gene whose product can pair with the DRα chain)

1) Polygenic:

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Many genes within the MHC locus participate in antigen processing, antigen presentation or innate/adaptive immune response.

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2) Polymorphic:

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The MHC alleles (a pair of gene) are heterozygous and codominant (the protein products of both the alleles at a locus being expressed in the cell).

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Polymorphism + Polygeny = The MHC diversity

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The MHC restriction:- T cell receptor recognizes a conformation of a self-MHC + antigen complex

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The benefits of MHC diversity:1. Minimizes chances for pathogens to evade the MHC detection.

2. Reduces the likelihood that a pathogen will be able to block antigen presentation by inhibiting the MHC function.