major histocompatibility complex (mhc) and tcr
TRANSCRIPT
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LOGO
Riandini Aisyah
March 2010
Major HistocompatibilityComplex (MHC) and T Cell
Receptors
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Principles of Immne Response
Highly specific recognition of foreign antigens
Mechanisms for elimination of microbes bearing
such antigensA vast universe of distinct antigenic specifies
Immunologic memory
Tolerance of self-antigens
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200!11!2" #ystem $iology
Major Histocompatibility Complex
(MHC)
Transfer of information about proteins %ithin a
cell to the cell surface
MH& I are e'pressed on the great ma(ority ofcells and recogni)ed by &*+, T cells
MH& II are e'pressed on $ cells macrophages
dendritic cells and recogni)ed by &*., T cells
Responsible for graft re(ection
/ound on chromosome " in human and 1 in
mouse
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Historical !ac"#rond
There %ere three inds of molecules encoded bythe MH& &lass I
&lass II
&lass III
&lass I MH& molecules are found on allnucleated cells not R$&s3
&lass II MH& molecules are found on A4& *endritic cells Macrophages $ cells other cells
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Historical !ac"#rond
Class I MHC
Class II MHC
R!Cs
$PCs
%cleated cells
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&i#re '*
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&i#re +
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,trctre of Class I MHC
T%o polypeptidechains a long 5 chainand a short 6 62microglobulin3
/our regions &ytoplasmic region
containing sites forphosporylation and
binding to cytoseletalelements
Transmembrane regioncontaining hydrophobicamino acids
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,trctre of Class I MHC
/our regions A highly conserved 5
domain to %hich &*+binds
A highly polymorphicpeptide binding regionformed from the 51 and52 domains
72-microglobulin helpsstabili)e theconformation
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,trctre of Class II MHC
T%o polypeptide
chains5 and 6 of
roughly e8ual length
/our regions &ytoplasmic region
containing sites for
phosporylation and
binding tocytoseletal elements
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,trctre of Class II MHC
/our regions Transmembrane region
containing hydrophobicamino acids
A highly conserved 52and a highly conserved62 domains to %hich&*. binds
A highly polymorphicpeptide binding regionformed from the 51 and61 domains
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&i#re +'
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&i#re +-
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Important $spects of MHC
Although there is a high degree ofpolymorphism for a species an individual hasma'imum of si' different class I MH& productsand only slightly more class II MH& products
considering only the ma(or loci39 :ach MH& molecule has only one binding site9
The different peptides a given MH& moleculecan bind all bind to the same site but only oneat a time9
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Important $spects of MHC
$ecause each MH& molecule can bind manydifferent peptides binding is termeddegenerate9
MH& polymorphism is determined only in thegermline9 There are no recombinationalmechanisms for generating diversity9
MH& molecules are membrane-bound;
recognition by T cells re8uires cell-cell contact9
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Important $spects of MHC
Alleles for MH& genes are codominant9
:ach MH& gene product is e'pressed on the
cell surface of an individual nucleated cell9
A peptide must associate %ith a given MH& ofthat individual other%ise no immune response
can occur9 That is one level of control9
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LOGO
T cell acti.ation
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Mature T cells must have a T cell receptor that
recogni)es the peptide associated %ith MH&9
This is the second level of control9
&ytoines especially interferon-
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4eptides from the cytosol associate %ith class
I MH& and are recogni)ed by Tc cells 9
4eptides from %ithin vesicles associate %ith
class II MH& and are recogni)ed by Th cells9 =hy so much polymorphism>
#urvival of the species
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&i#re +/
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&i#re +0
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&i#re +0 part of /
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&i#re +0 part / of /
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&i#re +1
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200!11!2" #ystem $iology
One Receptors2 T3o 4inds of ,i#nals
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200!11!2" #ystem $iology
Peptides !indin# to MHC Molecles
MH& I molecules bind short peptides usually
bet%een + and 10 residues9
The typical length of a class I ligand comprises ?
amino acids9
&lass II ligands consist of 12 to 2@ amino acids9
A core of nine amino acids is essential for
peptide!MH& binding9
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200!11!2" #ystem $iology
MHC peptide prediction
nderstanding the basis of immunity
*evelopment of peptide vaccines
Immunotherapeutics for cancer and autoimmunedisease
#everal mathematical approaches for MH&
peptide binding prediction
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&ertain MH& molecule binds the corresponding
anchor residueof antigenic peptides9
Antigenic peptides %hich can combine %ith
the same ind of MH& molecule have same or simular
anchor sites and anchor residues
consensus motif39
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NH2 Ag peptide
Anchor
residueAnchor site
MHC-II moleculeMHC-II molecule
C00H
&omparison of anchor sites and anchor
residues in class I and II MH& molecules
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19There are more anchor sites in class II MH&
molecules than that in class I MH& molecules9
29 Amino acid varieties of anchor residues in class II
molecules are more than that in class I MH&
molecules9
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,trctre of t5e T cell Receptor
:ach T cell bears
T&Rs of only one
specificity allelic
e'clusion3
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Or#ani6ation and Rearran#ement of t5e T Cell
Receptor
78 rearran#ement
89 rearran#ement
Transcription
Germline -C5ain Gene7L
P
Vn7/L
P
L
P
8 911--------J16 D2C1 911---------------J17 C2
:
8%$
7L
P
Vn7/L
P
L
P
D191 C1 D2 911---------------J17 C2
:
7L
P
L
P8%$
V2D191 C1 D2 911---------------J17 C2
:
R%$
V2D19
1 C1
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Comparison of TCR and !CR
4roperty $&R sIg3 T&RBenes
Many C*Ds /e% &s Ees Ees
C*D rearrangement Ees Ees
C regions generate Ag-binding site Ees Ees
Allelic e'clusion Ees Ees
#omatic mutation Ees Fo
4roteinsTransmembrane form Ees Ees#ecreted form Ees Fo
Isotypes %ith different functions Ees Fo
Calence 2 1
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C5aracteristics of interaction
19 Relative specificity
29 /le'ibility
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!iolo#ical fnctions of MHC
4articipate in processing and presenting ofantigen
4articipate in controling cell-cell recognition inimmunoreaction
4articipate in genetic control for immuneresponse
4articipate in inducing the differentiation anddevelopment of T cell in thymus
4articipate in inducing allograft re(ection
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I; Participate in processin# and presentin# of
anti#en
:ndogenous antigenGantigens synthesi)ed
%ithin cells
:'ogenous antigenGantigens comes outsidethe cell
:ndogenous Ag is presented to &*+,T cell
by MH& class I molecule:'ogenous Ag is presented to &*.,T cell by
MH& class II molecule
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CD4+T cell(Th) CD8+T cell(Tc)
T cellReceptor
Peptide
MHCClass II
T cellReceptor
Peptide
MHCClass I
Antigen PresentingCell
Antigen PresentingCell
CD4 CD8
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II; Participate in controlin# cellcell reco#nition in
immnoreaction
MHC restriction
In interaction of T cell and antigen-presenting
cellA4&3 or target cellT cell not only recogni)esspecific antigen peptidebut also recogni)es
polymophic residue of MH& molecules9That is to
say interaction of T cell and antigen-presenting
cellA4&3 or target cell need restriction by MH&molecules9 -----MH& restriction
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In interaction of Th cell and antigen-presenting cellA4&3 is restricted by class IImolecules9
In interaction of Tc cell and antigen-presenting cellA4&3 or target cell is restricted
by class I molecules9
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&i#re +0
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&i#re +