MHC: The antigen-presenting receptorsMHC: The antigen-presenting receptors

Antigen-presentingcell (M, LB, dendritic cell)

MHCEpitope: Ag fragment

Ag receptor

Antigen-sensitive cell(T cell CD4, CD8)

The key role of MHC molecules in presenting antigens to antigen-sensitive cells

0

The Major Histocompatibility ComplexThe Major Histocompatibility Complex

MHC restriction

CLASS ICLASS I CLASS IICLASS II CLASS IIICLASS III

Receptors for endogenousReceptors for endogenous Ag (nucleted cells)Ag (nucleted cells)Not found on gametes, Not found on gametes, neurons.neurons.

Receptors for exogenousReceptors for exogenousAg (APC)Ag (APC)

A mixed group of proteinsA mixed group of proteins(including C´components)(including C´components)

The three major classes of genes within the MHCThe three major classes of genes within the MHC

chromosomechromosome

The Major Histocompatibility ComplexThe Major Histocompatibility Complex

COMPARISON OF MHC CLASS I AND MHC CLASS II MOLECULESCOMPARISON OF MHC CLASS I AND MHC CLASS II MOLECULES

CLASS IaCLASS Ia CLASS IICLASS II

Loci Loci A, B and CA, B and C DP,DQ, DR, DP,DQ, DR, DO and DNDO and DN

Method ofMethod ofdetectiondetection

SerologySerology Serology and mixedSerology and mixedlymphocyte reactionlymphocyte reaction

DistributionDistribution Nucleated cellsNucleated cells B cells, macrophagesB cells, macrophagesand dendritic cellsand dendritic cells

FunctionFunction Present Ag to citotoxicPresent Ag to citotoxicT cells (CD 8)T cells (CD 8)

Present Ag to helper Present Ag to helper T cells (CD4)T cells (CD4)

ResultResult CitotoxicityCitotoxicity CooperationCooperation

Peter C. Doherty, DVM.Australia

St. Jude Children's Research Hospital Memphis, TN, USA

b. 1940

Rolf M. ZinkernagelSwitzerland

University of Zurich, Institute of Experimental Immunology

Zurich, Switzerland b. 1944

1996, Nobel Prize for Medicine

Transmembrane

1 2

3 2mIg domain

Citoplasmic

A three-dimensional representation of a class I MHC moleculeon a cell membrane

Binding site toT cells

alpha

2m beta 2 microglulin

MHC Class INucleated cells

Peptide-bindinggroove

2-micro-globulin

Peptide

MHC Class I

Lateral view

Top view1 2

3

1

2

1 1

2

Transmembrane

Ig domain

Citoplasmic

Binding site toT cellsPeptide-binding

groove

The overall structure of an MHC class II molecule

MHC Class IIAntigen-presenting cells

1

2

MHC class II molecule

Peptide

1

2

Cleft is made of both and chains

1

Cleft geometry

MHC class I accommodatepeptides of 8-10 amino acids

-M

-chain

Peptide

MHC class II accommodatepeptides of >13 amino acids

-chain

-chainPeptide

MHC IMHC I MHC IIMHC II

11 22

33 2m2m

11 11

22

TcTcCD 8CD 8

ThThCD 4CD 4

EndogenousEndogenouspeptidespeptides

ExogenousExogenouspeptidespeptides

CitotoxicityCitotoxicity Humoral Humoral responseresponse

Cellular Cellular responseresponse

ACCEPTED

Inbred mouse strains - all genes are identical

Transplantation of skin between strains shows thatrejection or acceptance is dependent upon

the genetics of each strain

Skin from an inbred mouse grafted onto the same strain of mouse

REJECTED

Skin from an inbred mouse grafted onto a different strain of mouse

Genetic basis of transplant rejection

Transplant rejection is due to an antigen-specific immune responsewith immunological memory.

Primary rejection of strain skin e.g. 10 days

Secondary rejection of strain skin e.g. 3 days

Primary rejection ofstrain skin e.g. 10 days

CD8Transfer lymphocytesfrom primed mouse

Immunological basis of graft rejection

6 months

…And the MHC Class III?...

CLASS I CLASS II CLASS III

Receptors for endogenous Ag (nucleated cells)

Receptors for exogenousAg (APC)

A mixed group of proteins

The three major classes of genes within the MHC

chromosome

C4, C2, B, TNF- and ,Heat shock protein 70 (HSP 70)

C4 C2 B 21-OH TNF TNF HSP

LiverM

Adrenal M Many cells

Hostdefenses

Steroidbreakdown

Tumor celldestruction

ProtectionVs

damage

Productionsite

Function

The overall arrangement of genes within the mouse MHC class III region

MHC Class III

FatherFather

MotherMother

FatherFather

MotherMother

The optimal number of MHC molecules

2 4 6 8 10 12Number of MHC genes

Susceptibility toinfection

Risk of autoimmunity.

Regulation of Immune Response by MHC.

MHC Restriction

MHC molecules act to regulate the immune response

ImmuneImmuneresponseresponse

No immuneNo immuneresponseresponse

Antigen

MHC gene B

APC

CD4

MHC class II

MHC gene A

APC

CD4