Major Histocompatibility Complex (MHC) and TCR

7/24/2019 Major Histocompatibility Complex (MHC) and TCR

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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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$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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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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One Receptors2 T3o 4inds of ,i#nals


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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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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 +

Major Histocompatibility Complex (MHC) and TCR

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