lecture 4 - MHC and antigen presentation

intracellular pathogens vs extracellular pathogens

intracellular pathogens reside and replicate inside a cell, extracellular pathogens replicate outside of cells.

intravesicular pathogens reside where?

they are degraded by? why?

antigens/peptides bind to MHC class __?

they are presented to what cells?

= activation to ___ intravesicular bacteria/parasites

vesicles within a cell

endocytic vesicles. they have a low (acidic) pH

II

effector CD4 T cells

kill

cytosolic pathogens reside where?

the pathogen is degraded where?

the peptides bind to MHC class __

the peptides are presented to which cells?

the effect on the presenting cell?

cytosol

cytosol

I

effector CD8 T cells

cell death due to cytotoxic T cells

extracellular pathogens and toxins reside where?

they are degraded where?

the peptides bind to MHC class __

they are presented to what cells?

what is the effect on the presenting cell?

outside of a cell

endocytic vesicles (they have a low (acidic) pH)

II

effector CD4 T cells

activation of B cells to secrete Ig to eliminate the pathogen

whilst MHC class I molecules are translated, they are _______ into the __ membrane

pathogens are being degraded by the ________ in the cytosol

the peptides are ______ transported from the cytosol to the ER by the ___ complex

embedded

ER

proteasome

actively

TAP

steps of MHC class 1 to be expressed on cell membrane.

1. partially folded MHC class I binds to calnexin for B2-microglobulin to bind

2. MHC class I aB2m complex binds to calreticulin, ERp57 and tapesin

3. this complex binds to TAP via tapesin

4. defective ribosomal products (DRiPs), old proteins and degraded peptide from proteasome are delivered to ER by TAP

5. peptide binds to MHC class I - full complex is released from TAP and exported to cell membrane

adenovirus protein ___ inhibits peptide loading onto MHC class I by _________

E19

competing with tapasin, blocking the complex from binding to TAP

where are MHC class II molecules presented?

vesicles

steps of extracellular antigens being presented onto MHC class II peptides

1. antigen taken up into intracellular vesicles

2. as endosome matures, pH decreases

3. low pH activates proteases to degrade antigen into peptide fragments

4. MHC class II is synthesised in ER and binds to an invariant chain (Ii)

5. Ii is cleaved in acidic endosome leaving CLIP (Class-II associated Invariant chain Peptide)

6. vesicles containing peptides fuse with vesicles containing MHC class II

7. HLA-DM binds to MHC class II releasing CLIP

8. peptide fragments can bind to MHC class 11 groove

9. MHC class II travels to cell surface

what is Invariant Chain (Ii)?

• what does it bind to?

• what is it’s purpose?

a trimer which binds to 3 Class II aB molecules in the ER

binds to MHC class II’s groove

prevent premature peptide binding

what happens if virus doesn’t infect APCs?

• Class I (normally presents intracellular antigens) → what if antigen is outside of the cell?

• Class II (normally presents extracellular antigens) → what if antigen is within the/invaded cell?

• partially degraded antigens in endosomal pathway can be translocated to cytosol

• cytosolic proteins can be loaded by autophagy

cross-presentation of exogenous antigens

1. extracellular antigen uptake by phagocytosis into endosome

2. antigen degraded into peptides in cytosol OR antigen is loaded into preformed MHC class I in an endosomal compartment

3. degraded peptides loaded into ER to load onto MHC class I

presentation of cellular antigens by MHC class II

1. antigen broken down in autophagosome then enters MHC Class II pathway

HLA (_______ ______ _______) encodes for ___ region

class I section is made up of ____, ____ and, ____

class II section is made up

• DP, DQ and ___ which make up the MHC II protein chains

• DOA and DOB which make ______ which kicks out CLIP

• TAPBP and TAP which are involved in ______

human leukocyte antigen

MHC

HLA-A, HLA-B, HLA-C

DR

HLA-DM

MHC class I binding

MHC restriction is?

T cells only recognising specific antigens when bound to self-MHC molecules

superantigens circumvent normal recognition. how? and why so dangerous?

they bind outside of MHC and to the T cell receptor (TCR)

non-specific binding regardless of antigen causes massive T cell activation/inflammatory response - e.g. toxic shock syndrome

what characteristic enable MHC antigen diversity?

MHC class I and II genes are highly polymorphic - many allelic variation between each genes (i.e. DRB in MHC Class II, HLA-A in MHC Class I)

inherit two MHC class regions from each parent - haplotype

• 6 versions of MHC I

• 6-8 types of MHC II

they are polygenic - inheriting multiple genes that encode for MHC class 1

so I inherit 6, only 1 is required for 1 MHC 1 molecule but each 1 has many different alleles