• Group of antigens first identified in graft patients

• Important in determining the compatibility of tissues in successful grafting

• Major histocompatibility antigens are glycoproteins found in the membranes of most cells of vertebrate animals

• Function to hold and position antigenic determinants for presentation to T cells

Major Histocompatibility Complex (MHC)

Historical Background

• Genes in the MHC were first identified as being important genes in rejection of transplanted tissues

• Genes within the MHC were highly polymorphic

• Studies with inbred strains of mice showed that genes within the MHC were also involved in controlling both humoral and cell-mediated immune responses– Responder/Non-responder strains

Historical Background

• There were three kinds of molecules encoded by the MHC– Class I– Class II– Class III

• Class I MHC molecules are found on all nucleated cells (not RBCs)

• Class II MHC molecules are found on APC– Dendritic cells, Macrophages, B cells, other

cells

Historical Background

Class I MHC

Class II MHC

RBCs

APCs

Nucleated cells

MHC Molecules• Major histocompatibility antigen

– Body cell surface proteins coded by a family of highly polymorphic genes

– MHC class I: found on all nucleated cells

– MHC class II: found only on APCs

• T cell receptors recognize antigenic peptide/MHC complexes– CD4+ T cells: restricted by class II

– CD8+ T cells: restricted by class I

Figure 16.11

• T-independent antigen– Large antigen molecules with readily accessible, repeating

antigenic determinants

– B cells can bind these directly without being processed• Stimulates B cells to differentiate into a plasma cell and produce antibodies

Antigen Processing

• T-dependent antigens– Smaller antigens with less accessible antigenic determinants

– B cells require involvement from helper T cells to target these antigens

– Helper T cells are assisted by leukocytes that process the antigen to make the antigenic determinants more accessible

• Processing is different based on whether the antigen is exogenous or endogenous

Antigen Processing

• APC internalizes the invading pathogen and enzymatically digests it into smaller antigenic fragments which are contained within a phagolysosome

• Phagolysosome fuses with a vesicle containing MHCII molecules

• Each fragment binds to the antigen-binding groove of a complementary MHCII molecule

• The fused vesicle then inserts the MHCII-antigen complex into the cytoplasmic membrane so the antigen is presented on the outside of the cell

Processing of Exogenous Antigens

• The intracellular pathogens are also digested into smaller antigenic determinants

• Each fragment binds to a MHCI molecule located in the endoplasmic reticulum membrane

• The membrane is packaged into a vesicle by a Golgi body which is inserted into the cytoplasmic membrane so the antigen is displayed on the cell’s surface

Processing of Endogenous Antigens

Roy, 2003 (www)

Endogenous and Exogenous Antigen Presenting PathwaysEndogenous and Exogenous Antigen Presenting Pathways

Immune System. In: Encyclopedia of Life Sciences (www)

Endogenous and Exogenous Antigen Presenting PathwaysEndogenous and Exogenous Antigen Presenting Pathways

• Sites at which grafts are not likely to be rejected• Different sites are privileged for different reasons

– The brain lacks lymphatic vessels, and its blood vessel walls are impermeable to lymphocytes such as T cells

– Cornea lacks extensive blood vessels

– Eyes and testes contain naturally high levels of immunosuppressive molecules

– Other sites either lack dendritic cells or express low levels of MHC molecules, so antigen processing does not occur

Privileged Sites

• The fetus is not a privileged site but is not rejected

• Rejection is prevented by the many different immunosuppressive mechanisms– Early embryos do not express MHC class I and II molecules

on the placental layer that is in contact with maternal tissues

– Cytokines that enhance MHC expression have no effect on placental cells

– T cells are prevented from functioning in the placenta to reject the fetus

Why Fetuses are Not Rejected

Immune Evasion ExamplesImmune Evasion Examples

Mycobacteria : Inhibits phagolysosome fusion so that it survives within the phagosome

Herpes simplex virus : Interferes with TAP transporter (inhibits antigen presentation)

Cytomegalovirus : Inhibits proteasome activity and removal of MHC I from EREpstein-Barr virus : Inhibits proteasome activity; produces IL-10 to inhibit

macrophage activationPox virus : Produces soluble cytokine receptors to inhibit activation of

effector cells

Structure of Class I MHC

NH2

Alloantigenicsites

CHO

NH2

COOH

COOH

P

α1

α2

α3

β2

OH

Plasma membrane

Disulfide bridge

Papain cleavage

Cytoplasm

NH2

Structure of Class I MHC Peptide-binding Region

• a “groove” composed of an α-helix on two opposite walls and eight β-pleated sheets forming the floor

• residues lining groove most polymorphic

• peptide in groove 8-10 amino acids long

• specific amino acid on peptide required for “anchor site” in groove

Structure of Class II MHC

Plasma membrane

Cytoplasm

CHO

CHO

CHO

NH2 NH2

COOH COOH

α1

α2 β2

β1

Structure of Class II MHC• Two polypeptide chains, α and β, of

roughly equal length. 1. Peptide-binding region – a groove

formed from the α1 and β1 domains of the α and β chains – site of polymorphism

2. Immunoglobulin-like region – conserved α2 and β2 domains – β2 is site to which CD4 on T cell binds

• Both have a peptide-binding groove with a wall of two α helices and a floor of eight β-pleated sheets

• Close-ended groove for class I MHC requires an 8-10 amino acid-length peptide to bind; open-ended groove for Class II MHC lets it bind a peptide 13-25 amino acids long, not all of which lie in the groove

• Anchor site rules apply to both classes

Peptide-binding grooves for class I and class II MHC are

structurally similar

The human MHC genesThe human MHC genes

class II c lass ID P D Q D R B C A

B C A

D P D Q D R

1 2 2 2 1 1 9 3 1 2 2 1 3

Class I polymorphism

Locus

Number of alleles

(allotypes)

HLA - A 218

HLA - B 439

HLA - C 96

There are also HLA - E, HLA - F and HLA - G

Relatively few alleles

Class II polymorphism

Locus

Number of alleles

(allotypes)HLA - DPA

HLA - DPB

12

88

HLA - DQA

HLA - DQB

17

42

HLA - DRA

HLA - DRB1

HLA – DRB3

HLA – DRB4

HLA – DRB5

2

269

30

7

12

There are also HLA - DM and HLA - DO Relatively few alleles

Comparison: MHC Class I and II Structure

Role of CD4 and CD8 in promoting T-cell responses

Costimulation is Necessary for T Cell Activation

• Engagement of TCR and Ag/MHC in the absence of costimulation can lead to anergy

• Engagement of costimulatory molecules in the absenece of TCR engagement results in no response

• Activation only occurs when both TCR and costimulatory molecules are engaged with their respective ligands

• Downregulation occurs if CTLA-4 interacts with B7– CTLA-4 send inhibitory signal

T cell selection/education:

MHC Restriction:

• Property of T cells to recognize antigens presented only by self-MHC molecules

• Vital aspect of self/non-self discrimination and hence adaptive immunity

• A marker of T cell that has been positively selected

• Selection occurs in the thymus

MHC restriction of immune response

MHC-TCR recognition of antigen

Dendritic Cell

• Most potent APC for naïve T cells

• Many long membrane extensions

• Highly variable depending on location– Langerhan cells in the skin

– Interdigitaing cells in the thymus

– FDC in germinal centers

– Veiled cells in lymphatics

– Blood dendritic cells in circulation

Only mature DC activates T cells

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are needed to see this picture.

Activation/ProliferationT cellMature DC

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.Anergy/Apoptosis/DeletionT cellImmature DC

Functions of APCs

• T cell selection in the thymus (only DCs)• Trap and capture antigen in the periphery• Process antigen into peptides• Store antigens • Transport antigens to peripheral lymphoid tissues• Present antigenic peptides to T cells• Co-stimulate T cells

T Cell Activation• Requirements: Two signals

– Signal 1: specific recognition of antigen (peptide-MHC complex) via antigen receptor

– Signal 2: costimulatory signals from APC

• Signal 1 alone leads of unresponsiveness– Anergy, Deletion, Apoptosis

Structure of T Cell Receptor

CHO CHO

CHOCHO

Variable region “V”

Constant region “C”

Hinge “H”

Alphachain

Betachain

Disulfide bridge

Transmembrane region

Cytoplasmic tail

++ +

Structure of T Cell Receptor (TCR)

• Two polypeptide chains, α and β, of roughly equal length

• Both chains consist of a variable (V) and a constant (C) region

• α chain V region has a joining (J) segment

• β chain V region has both a J and diversity (D) segment

Structure of T Cell Receptor(continued)

• Hypervariable regions in V contribute to diversity of TCR

• TCR recognizes portions of MHC molecule and peptide bound in the groove

• Small population of T cells has a TCR comprised of γ and δ chains – γδ TCR specificity differs from αβ TCR

Accessory Molecules

• All are invariant

• Increase adhesion between two engaged cells

• Some show increased expression in response to cytokines

Costimulatory Molecules

• Molecules on T cell and 2nd cell that engage to deliver 2nd signal required for activation of T cell

• Most important costimulatory molecules:

T cell Ligand on 2nd cell

CD28 B7-1 (CD80), B7-2 (CD86)

Interactions of Th Cell and APC

LFA-3

LFA-2 LFA-1 TCR

CD4

ICAM-1 Class IIMHC

B7-1/B7-2(CD80/CD86

CD28

IL-1IL-6TNF-alphaIL-12IL-15

TNF-betaIFN-gammaGM-CSFIL-4

T helperlymphocyte

Antigen-presenting

cell

peptide

Interactions of Tc Cell and Target Cell

LFA-1 TCR

CD8

ICAM-1 Class IMHC

LFA-3

LFA-2T cytotoxiclymphocyte

Targetcell

peptide

Aspects of MHC1. MHC molecules are membrane-bound. Recognition

by T cells requires cell-cell contact.2. Peptide from cytosol associates with class I MHC

and is recognized by Tc cells. Peptide from vesicles associates with class II MHC and is recognized by Th cells.

3. Although there is a high degree of polymorphism for a species, an individual has maximum of six different class I MHC products and only slightly more class II MHC products

4. Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. This is the second level of control.

4. Each MHC molecule has only one binding site. The different peptides a given MHC molecule can bind all bind to the same site, but only one at a time.

5. MHC polymorphism is determined only in the germline. There are no recombinational mechanisms for generating diversity.

6. Because each MHC molecule can bind many different peptides, binding is termed degenerate.

7. Cytokines (especially interferon-γ) increase level of expression of MHC.

8. Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell.

HLA and disease associationHLA and disease association

Disease Associated alleles Frequency in

Relative riskpatients control

Ankylsoing spondylitis

Reiter’s disease

Acute anterior uveitis

Psoriasis vulgaris

Dermatitis herpetiformis

B27

B27

B27

CW6

DR3

9

79

52

87

85

9

9

9

33

26

87.4

37.0

10.4

13.3

15.4