AG presentation

• Tcells - thymus derived

• T cells are crucial to control intracellular pathogens

• needed to activate B cells for AB production against most AGs

cytosolic pathogens

Degraded in: Cytosol

Peptides bind to; MHC class 1

Presented to: CD8 T cells

Effect on presenting cell: Cell death, altruistic, need to present peptide which are in the cytoplasm -> Viruses mainly in cytoplasm

intravesicular pathogens

degraded in: endocytic vesicles (Low PH)

peptides bind to: MHC class 2

Presented to: CD4 Tcells

Effect on presenting cell: activation to kill intravesicular bacteria and parasites -> bacteria in vesicles -> mycobacterium (m.tuberculosis, m-leprose)

with respiratory burst -> always tissue damage

How do macrophages kill? Tcell endocytosis, lysis, acidification

extracellular pathogens and toxins

degraded in: endocytic vesicles (Low PH)

peptides bind to: MHC class 2

presented to: CD4 Tcells (gives help to activate the B cell)

effect on presenting cell: activation of B cells to secrete IG to eliminate extracellular bacteria/toxins (produce ABs)

can uptake pathogens

DC and macrophages - everywhere

B-cells recognize pathogens via circulation

mature DC distingusih from the inmature DCs

-> getting in contact with naive T-cells -> scanning progress

T cell-mediated immune responses are based on direct interactions between Tcells and AG-presenting cells -> cell-cell contact in draining lymph node.

T helper cells (TH1,TH2) -> CD4+

cytotoxic T cells -> CD8+

in both cases, Tcells recognize their target cells by binding to peptide fragments derived from foreign proteins (pathogens) presented by either MHC-1 (for CD8+ T cell activation) or MHC-2 (for CD4+ Tcell activation

• membrane-bound glycoproteins that present peptide AGs to T cells

• important to maintain “histocompatibility” after transplantation of tissue and organs

• “histocompatibility complex”: highly polmorphous gene cluster encoding for several MHC molecules -> not one single gene

• most highly diverse gene complex in human genome

the size of peptides that are bound in the binding pocket of MHC-1 and MHC-2 molecules is different:

MHC-1 peptide-> 8-10 AS -> depends on strucutre of the binding pocket

MHC-2 peptides -> 13-18AS

Both are aß heterodimers, but with different structures due to different a and ß-polypeptide chains used:

MHC-1 - a-subunit (encoded by polymorphous MHC locus), ß subunit (not encoded by MHC locus) -> ß2 micrpglobulin (ß2m) higly conserved

• only a unit is responsible for peptide binding

  ß is only responsible for propper folding (highly conserved)

MHC-2 a subunit & ß subunit - encoded by MHC locus, both contribute to peptide binding

-> in principle unlimited length

only a, consisting of 3 chains - peptide binding

ß associated but not contributed to binding

• sequnce is different

• conserved ancher residues

• all peptides (8-10) can be presented

• length of peptide is limited up to 10AS

• finding: destrice and explain- letter code of AS. green - binding point. different peptides, one MHCI can bind to different peptides.

• conserved residues detected

• no ancher residues

• totally different lenght in peptides

• Acidic ASs are conserved - can present a variety of the peptides

• aliphatic/neutral ASs

binding and presentation of AG peptides at the cell surface to be recognized by T cell receptors expressed ba AG-specific Tcells

MHC1 and MHC2 molecules have different properties in activating T cells:

MHC1 presents peptides to cytotoxic Tcells, these express CD8 and MHC1 binds to CD8. - fate: death

MHC2 presents peptides to THcells, these express CD4 and MHC2 binds to CD4. - fate: activation of T cell

consider Tcell- MHCII als a minus

MHC1 MHC2

Expression: all nucleated c.in the body restricted to prof. AG-pres. cells

Activation: of CD8+ T cells of CD4+ T cells

Gene loci: HLA-A, HLA-B, HLA-C HLA-DR, HLA-DP, HLA-DQ

Strucutre: transm. a chain. transm. heterodimer consisting

assosiated with ß2-microglob. of a & b-chain

Peptide size: max 8-10 AS at least 13-18AS

Loading: in the ER in intracellular vesicles

Glycoproteins- membrane proteinse

-> synthesized in ER and later in Golgi

MHC-1 molecules present peptides from viruses -> CD8 gives signal to kill

viruses replicate in cytoplasm -> problem for loading peptides = need to get to the ER

chaperones help by transport

• Partially folded MHC 1 a chain bind to calnexin until ß2microglobulin binds->

• MHC1 a:ß2-m complex is released from calnexin, binds a complex of chaperone proteins (calreticulin, Erp57) and binds to TAP via tapsin ->

• cytosolic proteins are degraded to peptide fragments by the proteasome, a large multicatalytic preotease ->

• TAP (transporter assosiated with a protein receptor) delivers a peptide that binds to the MHC class 1 molecule and completes its folding. the fully folded MHC1 molecule is released from the TAP complex and exported

• mediated by an active (ATP-dependent) Process. -> controlled

transporter associated with AG prossessing

strategies of viruses to interfere with AG pres. of viral peptides

HPV: prevents transport of viral peptides into the ER by expression of a protein that binds to and inhibits the TAP transporter

Adenovirus: encodes a protein that leady to retaining of MHC1 molecules in the ER

Cytomegalovirus: accelerates the retrograde transport of MHC1 molecules into the cytosol where they are degraded

these viruses can evoid the MHCI molecules -> is this the end? How could the Immune system act against them? —> MHCI not present on the surface -missing self and NKcells can kill them.

MHCII presentation - in membrane/glycoproteins - can they be loaded in ER ? -> no! would be a mix up and they couldnt be discriminated! -> loading is in acidic vesicles!! -> where the peptides are generated.

endocytosis. AG is taken up into intracellular vesicles -> in early endosomes of neutral pH endosomal proteases are inactive -> acidification of vesicles activates proteases to degrade AG into peptide fragments -> vesicles containing peptides fuse with vesicles containing MHC class 2 molecules

How do these MHCII moldecules get there ? golgi-mediated transport

how can it be prefent that MHCII molcueles are loaded already with peptides in the ER where they are synthesised -> maybe ER has different chemical gradient and has an ‘Inhibitor’ -> chain! binding groove is blocked in the ER

CLIP= class 2 associated invariant chain peptide. => prevents the premature loading of MHC-2 molecules with peptides - MHC1 loaded with peptides in the ER

invariant chain (Ii) binds in the groove of MHC class 2 molecules -> it is cleaved initially to leave a fragment bound to the class 2 molecule and to the membrane (degrates by proteasis) ->further cleavage leaves a short peptide fragment. CLIP, bound to the class 2 molecule

invariant chain -> blocks the receptor

on the way to the ER - chain degraded and just one small point left to block the complex.

important components:

invariant chain:

a) binds to MHC2 aß heterodimer; blocks the binding pocket for other peptides ->prevents the loading of peptides in the ER -> invariant chain/MHC2 complex dissociates from calnexin and is then transported out of the ER => peptide binding pocket is still blocked by invariant chain

b) triggers transport of the complex to an endosomal vesicular compartment (so called MIIC = MHC"“ compartment) -> in the MIIC, the invariant chain is degraded by proteases -> binding pocket still blocked by the CLIP peptide (Clip stabiized MHC2). Then exchange by the pathogen derived peptides

3 genes for MHC1 - A, B, C

3/4 genes for MHC2 -> DP, DQ, DR (DO, DM) -> just 3 genes but 4 different possibles for MHCII bc 2 different ß chains

gene strucutre of the human MHC

Human leukocyte 1G - the whole thing

TAPBP - DP ß,a - DN a - DM a, ß - LMP/TAP (4) - DO ß - DQ ß,a - DR ß,ß,a (all this Class 2) ——- (class 3) —B—C——————A——(class 1)

polygeni - 3 genes

MHCII is a heterodimer and a and ß are encoded - this is why there are 2 bars

MHCI just a chain encoded

MHC molecules on high polymorphic gene cluster, there are many different possibilities bc of polygeni

• high number of many different numbers of allels - MHC polymorphism

• co-dominatn expression of MHC allels:

  • how many different MHC molecules can be on the surface ? -> only 6 (A,B,C) for MHC1, 8 for MHC2

  • random expression

• SNIPs- point mutations

• equally expressed on the cell surface

• the more MHC peptide - the more specific is the immune system

• possibility of autoimmunereaction

• higher costs with more MHC peptides

• a lot of genetic burden and also for production bc high energy costs

• variety of peptides increased with more genes

  
  

• 3 genes are “optimal” for humans, 2 for mice