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6_antigen_presentation.md

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Antigen presentation functions both in arming effector T cells and triggering effector functions

Cytotoxic T cells (CD8) engage with antigen presenting MHCI from the cytosol and kill cells

Effector T cells (CD4) engage with antigen presenting MHCII in endocytic vessicles.

Cytotoxic:

  • Direct presentation - cytosol -> ER -> MHCI
  • Cross presentation - take up from other cells

Effector:

  • Some effectors, eg. TH_1 cells, activate macrophages to kill pathogens replicating within them.
  • Autophagy - ingest pathogens from cytosol into

Peptides are generated from ubiquitinated proteins in the cytosol by the

Proteasome - multicatalytic protease:

  • 20S catalytic core
  • 2 19S regulatory caps

One cap shuttles proteins into the core and the other cap keeps proteins from leaving before they are degraded.

UPS system ubiquitination

lysine (target protein | ubiquitin) <> carboxy terminus of ubiquitin

This is assumed to be the main mechanism by which proteins are degraded for MHCI molecules

There is constitutive expression of proteasome core beta proteins, but:

  • immunoproteasome have beta proteins induced by interferon
  • thymoproteasome have beta protein crucial for CD8 T cell development

Defective Ribosomal Products (DRiPs)

  • improper splicing
  • translation of a frameshift
  • improperly folded Tagged with ubiquitin and degraded

Peptides from cytosol are transported into the ER by TAP to bind to MHCI

TAP are ATP-dependent peptide transporter spanning ER membrane (live in the MHC locus) Transports peptides between 8-16 aa in length

MHCI molecules chill in ER until they bind peptides

Calnexin is a chaperone protein that associated with alpha chain (as well as MHCII, TCR, IGX)

When a beta_2 binds to alpha, the complex disassociates from Calnexin and binds to another group of proteins to form Protein Loading Complex (PLC).

PLC:

  • calreticulin
  • tapasin - bridges with TAP to await a peptide
  • ERp57

What is peptide editing?

MHCI that are never associated with peptides are eventually ejected from the ER with the ERAD pathway (not specific to MHC-peptide association)

Dendritic cells use cross presentation

What if a virus never infects a non-dendritic cell? (Strange question because I'm sure that the)

Peptide:MHC II generated from acidified endocytic vesicles

MHC II present peptides generated from vessicles from dendritic cells, macrophages, B cells and present to CD4 T Cells.

MHC II molecules (like all membrane proteins) are deposited in ER and transported to membrane in ER buds, fusing with intracellular vessicles with antigens in them.

Peptides are ingested in different ways:

  • receptor mediated endocytosis by B cell surface immunoglobulin
  • macropinocytosis (not triggered by binding of cargo)

endosomes become increasingly acidic as they traverse towards the vesicles with MHCII

"acid proteases" play dominant role in antigen processing (are active 2-5 pH)

  • cathepsins
  • asparagine endopeptidase
  • IFN-gamma induced lysosomal thiol reductase Redundant and non-specific (chop things up without much precision)

The invariant chain directs MHC II to vesicles with peptides

Ii (invariant chain)

Winds through ER membrane and forms trimers with the inner head.

NH+3 < ER > CO-

CLIP (class II Associated Invariant Chain Peptide) Binds to the peptide binding groove

Trafficking of membrane proteins is associated with cytosolic sort tags, so the Ii ,

CLIP needs to be displaced from the MHC II

HLA-DM looks a lot like MHC-II and is found in the endosomal compartment. It binds to MHCII and causes it to change conformation and release peptide

HLA-DM also binds and rebinds to new peptide:MHC II complexes. This will get rid of peptides that are unstably bound. This is good because they need to last for days before interaction with a T cell.

HLA-DO is another molecule that looks like MHC II but is a negative regulator of HLA-DM

HLA-DM is to MHCII as tapasin is to MHC I

MARCH-1 stops antigen processing in dendritic cells during infection

MARCH (membrane associated ring finger) is an E3 ligase that ubiquinates cytoplasmic tail of MHC II

Constitutively expressed in B cells, dendritic cells, macrophages (the trinity that express MHC II).

During infection the pathway is shutdown

Also ubituinate CD86, a T cell co-stim.

MHC complex and function

Genetic structure of MHC

Class I

  • HLA-A
  • HLA-B
  • HLA-C

Class II

  • HLA-DP
  • HLA-DR
  • HLA-DQ

Non-classical MHC (Class Ib)

Interferon alpha, beta and gamma all increase transcription of MHC class I genes and associated chaperone proteins for antigen presentation.

Interferon gamma increases the MHC class II and chaperone proteins (including HLA-DM + HLA-DO that bind / help fix antigens in final processing steps)

Protein products of MHC class I / II are highly polymorphic

Polymorphism - across species, number of alleles in a gene.

Some MHC genes have > 1000 alleles.

  • Polygenic - multiple copies of gene on single chromosome
  • Polymorphic - lots of options for alleles. Increases likelihood of heterozygous genotype and therefore double the number of different MHC proteins
  • Codominant - express proteins from both sister chromosomes

The higher frequency of point (vs. silent mutations) than would occur by random chance points is evidence of selection for polymorphism

MHC polymorphism effects (1) antigen binding and (2) TCR binding

MHC isoforms have very high sequence divergence (20 amino acids) compared to other polymorphic genes

Most of this variability is in the peptide binding groove, effecting the anchor residues of classes of bindable peptides

If you do not have an appropriate MHC you cannot respond to the antigen. This is common in inbred individuals because they are homozygous for MHC genes

MHC restriction is the dependence of the TCR on both the antigen and the MHC complex when binding.

Peter Doherty + Rolf Zinkernagel

TCR only kill cells infected by specific virus (obvious) But will not kill cells infected by same virus but different MHC from that which primed it

Alloreactive T cell

Allogeneic T cells react to non self. Discovered from early mixed lymphocyte reactions. Pool two populations together and irradiate one so they cannot divide. 1-10% of all T cells will respond to cells from another individual in this way.

Alloreaction / alloreactivity - stems from recognition of allelic polymorphism

Two hypotheses:

  • Positive selection produces TCRs that bind to some MHC and increases likelihood that same TCR cross reacts to another MHC
  • Inherit property of TCR to bind to MHC (animals that lack MHC I / II and cannot positively

T cells respond to superantigens

Minor lymphocyte stimulating antigens (MLs) were found to stimulate T cells but were actually retroviral proteins stably integrated into mouse genome.

The response is useful to the pathogen not the host. It is not specific to the pathogen, so it binds a large number of T cells and causes massive production of cytokines by CD4 T cells - (1) systemic toxicity and suppression of further adaptive immune response.

(eg. toxic shock syndrome from staphylococcal bacteria)

Polymorphism allows diverse antigen binding

Why not more than 3/4 genes? Autoreactivity.

Self peptides that can bind vs. pathogen peptides that can bind.