Major Histocompatibility Complex Mhc and t Cell Receptors2334

7/23/2019 Major Histocompatibility Complex Mhc and t Cell Receptors2334

1/39

Major Histocompatibility Complex

(MHC) and T Cell Receptors


2/39

Historical Background

Genes in te MHC !ere "irst identi"ied asbeing important genes in rejection o"transplanted tissues

Genes !itin te MHC !ere iglypolymorpic

#tudies !it inbred strains o" mice so!ed

tat genes !itin te MHC !ere alsoin$ol$ed in controlling bot umoral andcell%mediated immune responses& Responder'on%responder strains


3/39


Tere !ere tree kinds o" moleculesencoded by te MHC& Class

& Class

& Class

Class MHC molecules are "ound on all

nucleated cells (not RBCs) Class MHC molecules are "ound on *+C

& ,endritic cells- Macropages- B cells- otercells


4/39


Class I MHC

Class II MHC

RBCs

APCs

Nucleated cells


5/39


Class MHC molecules& #ome complement components

& Transporter proteins


6/39


t !as not until te disco$ery o" o! te TCRrecogni.es antigen tat te role o" MHC genesin immune responses !as understood

& TCR recogni.es antigenic peptides in association !itMHC molecules

T cells recogni.e portions o" protein antigenstat are bound non%co$alently to MHC gene

products& Tc cells recogni.e peptides bound to class MHCmolecules

& T cells recogni.e peptides bound to class MHCmolecules


7/39


Tree dimensional structures o" MHC

molecules and te TCR a$e been

determined by /%ray crystallograpy


8/39

#tructure o" Class MHC

T!o polypeptidecains- a long 0 cainand a sort 1 (12microglobulin)

3our regions& Cytoplasmic region

containing sites "orposporylation and

binding to cytoskeletalelements

& Transmembrane regioncontaining ydropobicamino acids


9/39


3our regions&* igly conser$ed 04

domain to !ic C,5binds

&* igly polymorpicpeptide binding region"ormed "rom te 06 and02 domains

72%microglobulinelps stabili.e tecon"ormation


10/39


8ariability map o" Class 6 MHC 0 Cain


11/39


*g%Binding Groo$e

Groo$e composed o"an 0 elix on t!oopposite !alls andeigt 1%pleated seets"orming te "loor

Residues lining tegroo$e are mostpolymorpic

Groo$e accomodatespeptides o" 5%69amino acids long 3rom :ane!ay et al;- mmunobiology uired "or ?ancor

site@ in groo$e

& Many peptides can

bind

& 8accinede$elopment

3rom :ane!ay et al;- mmunobiology


13/39

Class polymorpism

Aocus

umber o" alleles

(allotypes)

HA* % * 265

HA* % B 4

HA* % C uires cell%cellcontact;


22/39

mportant *spects o" MHC

*lleles "or MHC genes are co-dominant;

=ac MHC gene product is expressed

on te cell sur"ace o" an indi$idual

nucleated cell; * peptide must associate !it a gi$en

MHC o" tat indi$idual- oter!ise no

immune response can occur; Tat isone le$el o" control;


23/39


Mature T cells must a$e a T cell

receptor tat recogni.es te peptide

associated !it MHC; Tis is te

second le$el o" control; Cytokines (especially inter"eron%I)

increase le$el o" expression o" MHC;


24/39


+eptides "rom te cytosol associate !it

class MHC and are recogni.ed by Tc

cells ; +eptides "rom !itin $esicles

associate !it class MHC and arerecogni.ed by T cells;

Jy so muc polymorpismK

& #ur$i$al o" te species


25/39

#tructure o" te T cell Receptor

Heterodimer !it one0 and one 1 cain o"rougly e>ual lengt

* sort cytoplamic tailnot capable o"transducing anacti$ation signal

* transmembraneregion !itydropobic aminoacids


26/39


Bot 0 and 1 cains

a$e a $ariable (8)

and constant (C)

region 8 regions o" te 0 and

1 cains contain

yper$ariable regions

tat determine te

speci"icity "or antigen


27/39


=ac T cell bears

TCRs o" only one

speci"icity (allelic

exclusion)


28/39

Genetic Basis "or Receptor Generation

Generation o" a $ast array o" BCRs isaccomplised by recombination o" $arious8- , and : gene segments encoded in te

germline Generation o" a $ast array o" TCRs is

accomplised by similar mecanisms& TCR 1 cain genes a$e 8- , and : gene

segments

& TCR 0 cain genes a$e 8 and : genesegments


29/39

Organization and Rearrangement of

the T Cell Receptor

-! rearrangement

!-" rearrangement

Transcription

#ermline -Chain #ene

$%

P

Vn&%

P

%

P

!$ "11--------J16 D2C1 "11---------------J17 C2

'

!NA

$%

P

Vn&%

P

%

P

D1"

15 C

1 D

2"

11---------------J

17 C

2

'

$%

P

%

P!NA

V2D1"

15 C1 D2 "11---------------J17 C2

'

RNA

V2D1"

15 C

1


30/39

Comparison o" TCR and BCR

+roperty BCR (sg) TCRGenes

Many 8,:s- 3e! Cs Les Les

8,: rearrangement Les Les

8 regions generate *g%binding site Les Les

*llelic exclusion Les Les

#omatic mutation Les o

+roteinsTransmembrane "orm Les Les

#ecreted "orm Les o

sotypes !it di""erent "unctions Les o

8alence 2 6


31/39

I TCR

#mall population o" T cells express a TCRtat contain I and cains instead o" 0 and1 cains

Te Gamma',elta T cells predominate inte mucosal epitelia and a$e a repertoirebiased to!ard certain bacterial and $iralantigens

Genes "or te cains a$e 8- , and :gene segments I cains a$e 8 and :gene segments

Repertoire is limited


32/39

I TCR

Gamma',elta T cells can recogni.e

antigen in an MHC%independent manner

Gamma',elta T cells play a role in

responses to certain $iral and bacerial

patogens


33/39

TCR and C,4 Complex

TCR is closelyassociated !it agroup o" D proteinscollecti$ely calledte C,4 complex& I cain

& cain

& 2 N cains

& 2 O cains

C,4 proteins arein$ariant


34/39

Role o" C,4 Complex

C,4 complexnecessary "or cellsur"ace expressiono" TCR during T cellde$elopment

C,4 complextransduces signalsto te interior o" tecells "ollo!inginteraction o" *g !itte TCR


35/39

Te ?mmunological #ynapse@

Te interaction

bet!een te TCR and

MHC molecules are

not strong *ccessory molecules

stabili.e te interaction

& C,'Class MHC or

C,5'Class MHC

& C,2'A3*%4

& A3*%6'C*M%6


36/39


#peci"icity "or antigen

resides solely in te

TCR

Te accessorymolecules are

in$ariant

=xpression is

increased in response

to cytokines


37/39


=ngagement o" TCR and*g'MHC is one signalneeded "or acti$ation o" Tcells

#econd signal comes "romcostimulatory molecules& C,25 on T cells interacting

!it BF%6 (C,59) or BF%2(C,5


38/39

Costimulation is Necessar( for T Cell

Acti)ation

=ngagement o" TCR and*g'MHC in te absence o"costimulation can lead toanergy

=ngagement o" costimulatorymolecules in te absenece o"TCR engagement results inno response

*cti$ation only occurs !enbot TCR and costimulatory

molecules are engaged !itteir respecti$e ligands

,o!nregulation occurs i"CTA*% interacts !it BF& CTA*% send inibitory signal


39/39

Pey #teps in T cell *cti$ation

*+C must process and present peptides to T cells

T cells must recei$e a costimulatory signal& Qsually "rom C,25'BF

*ccessory adesion molecules elp to stabili.e binding

o" T cell and *+C& C,'MHC%class or C,5'MHC class

& A3*%6'C*M%6

& C,2'A3*%4

#ignal "rom cell sur"ace is transmitted to nucleus& #econd messengers

Cytokines produced to elp dri$e cell di$ision& A%2 and oters

Major Histocompatibility Complex Mhc and t Cell Receptors2334

Documents