L3 Genetics of antigen recognition receptors (TCR and MHC)

what are TCR polypeptides encoded by

rearranging gene sequences

where do gene segments rearrange during T cell development

thymus

what are the mechanisms of generation of diversity of TCR

• multiple V,(D), and J segments

• combinatorial diversity: between V,(D) and J

• junctional diversity

when is TCR secreted

never

what gene sequences are at TCR alpha

V,J,C

what chromosome is TCRalpha on

14

what gene segments is TCRbeta on

V,D,J,C

what chromosome is TCRbeta on

7

what gene segments is TCRgamma on

V,J,C

what chromosome is TCRgamma on

7

what gene segments is TCRdelta on

V,D,J,C

what chromosome is TCRdelta on

14

what do TCR recognise

antigens in the groove of MHC molecules

describe MHC diversity

• no gene rearrangement occurs in MHC molecules

• co-dominantly expressed

where are MHC molecule genes located

within MHC (HLA in humans on chromosome 6)

where is class I MHC expressed

by all nucleated cells

where is class II MHC expressed

on particular cell types

• e.g. B cells, macrophages, dendritic cells, APC

what is class II up-regulated and induced by

interferon (inflammation)

what chromosome is MHC located

6

what are the most polymorphic genes

MHC molecules (many alleles)

how many MHC molecule does a single person have up to

12 (if they are heterozygous for all 6 MHC loci)

if they are heterozygous at each loci, how many different class I molecules can one person express

6

if they are heterozygous at each loci, how many different class II molecules can one person express

6

what are the MHC class I molecules

• HLA-A

• HLA-B

• HLA-C

what are the MHC class II molecules

• HLA-DP

• HLA-DQ

• HLA-DR

describe co-dominant expression of MHC molecules

polymorphism and polygeny

the location of polymorphic residue within MHC structure…

affects peptide binding

what does high levels of MHC polymorphism allow

the blinding of a vast range of peptides that can be presented to T cells

what does the blinding of a vast range of peptides that can be presented to T cells do

provides a clear evolutionary advantage to the population as they can respond to an almost unlimited no. of different pathogens

what is the downside of highly polymorphic MHC

• increases risk of immune-mediated disease

• reduces pool of available donor organs for transplantation

give an example of immune-mediated diseases related to highly polymorphic MHC

autoimmune diseases (increases likelihood of presenting self Ags.)

how does highly polymorphic MHC reduce the pool of available donor organs

MHC alleles on donor organ should match those of recipient for the best outcome

what are peptides that are derived from protein Ags synthesised inside a cell

endogenous Ag

• e.g. from an intracellular pathogen such as a virus

what are peptides that are derived from protein Ags synthesised inside a cell presented by

class I MHC molecules

what are peptides that are derived from protein Ags taken up from the outside of the cell

exogenous

• e.g. from an extracellular pathogen such as a bacterium/fungus

what are peptides that are derived from protein Ags taken up from the outside of the cell usually presented by

class II MHC molecules

for both endogenous and exogenous Ag, as MHC molecules present peptides, protein Ags need to be…

processed into small peptide fragments suitable for binding to and presentation by MHC (I and II) molecules

describe the steps of Ag presentation by MHC class I molecules

• Ag. (e.g. viral protein) synthesised in the cytoplasm

• protein cleaved to peptides by proteasome

• peptides transported to endoplasmic reticulum by TAP transporter

• peptides bind to MHC class I molecules

• MHC-1/peptide complex transported to cell surface

how does the proteosome function in all cells

cytoplasmic protein turnover

proteasomes in cells recieving inflammatory cytokines signals are modified to produce…

altered peptides

what is TAP a component of

a multi-protein assembly, the peptide loading complex

what does TAP contain

• tapasin

• calreticulin

what are cytosolic proteins degraded to peptide fragments by

proteosome

what is the proteosome

a large multicatalytic protease

TAP delivers a peptide that binds to the MHC class I molecule and completes its folding…

the fully folded MHC class I molecule is released from the TAP complex and exported

describe antigen processing and presentation by MHC class II molecules

• Ag. (e.g. bacteria) endocytosed into intracellular vesicles inside the cell

• protein cleaved to peptides by acid proteases in vesicles

• vesicles fuse with vesicles containing MHC class II

• peptides bind MHC class II molecules

• MHC-II/peptide complex is then transported inside vesicles to the cell surface

describe MHC class II in the endoplasmic reticulum

invariant chain (Ii) forms a complex with MHC class II molecule, blocking the binding peptides and misfolded proteins

describe MHC class II in the cytosol

Invariant chain is cleaved in an acidified endosome, leaving a short peptide fragment, CLIP, still bound to the MHC class II molecule

what happens to endocytosed antigens during exocytosis of MHC class II

endocytosed antigens are degraded to peptides in endosomes, but the CLIP peptide blocks the binding of peptides to MHC class II

what happens to HLA-DM during exocytosis of MHC class II

HLA-DM binds to the MHC class II molecule, releasing CLIP and allowing other peptides to bind. The MHC class II molecule then travels to the cell surface

what does MHC class II molecules binding to the invariant chain in the ER prevent

peptides binding in the groove

in the endocytic pathway, lysosomal enzymes degrade leaving what

CLIP peptide associated with the binding groove

what do peptides from the antigen displace when they bind

CLIP

what is HLA-DM, a class II-like molecule, required for

loading peptides into the groove

in normal healthy uninfected cells, what do MHC class I and MHC class II molecules bind and present peptides from

self proteins

what are accessory molecules involved in antigen processing and presentation encoded within

MHC

• discovered during sequencing of MHC

What pathway are TAP and LMP

class I

what pathway are HLA-DM

class II

as all nucleated cells express MHC class I molecules, any cell infected by a virus can prevent…

viral peptides on MHC class I molecules and be recognised and killed by cytotoxic CD8+ T cells

give examples of relatively few, specialised cell types which express MHC class II molecules

APC

• macrophages

• dendritic cells

• B cells

Take up and present extracellular Ag to activate helper CD4+ T cells

some other cell types can express MHC class II under certain conditions, what does this allow them to be recognised by?

helper CD4+ T cells