Antigen presentationand antigen presenting cell

The basic process of immune response

Antigenrecognition

Lymphocyteactivation

Effectorcells

Memorycells

YT

YB

antigenic peptide-MHC

BCR

native antigen

TCR

APC (antigen-presenting cell)

T cells do not recognize native antigens

Recognize antigen that has been degraded into antigenic peptides and displayed with MHC molecules on the cell surface

antigen processing and presentation

Antigen processing

Antigen presentation

CD4 T cell recognize peptide associated with MHC class II molecules

CD8 T cell recognize peptide associated with MHC class I molecules

Class I MHC molecule Class II MHC molecule

What determines whether an antigenic peptide associates with class I or with class II molecules?

It is dictated by the mode of entry into the cell, either exogenous or endogenous.

Class I MHC molecules bind peptides derived from endogenous antigens

Class II MHC molecules bind peptides derived from exogenous antigens

Exogenous antigen-is produced outside of the host cellenter the cell by endocytosis or phagocytosis

Endogenous antigen-is produced within the host cell itself

viral proteinstumor proteins

Two processing and presentation pathways

Endogenous antigens processed in the cytosolic pathway presented with class I MHC molecules

Exogenous antigens processed in the endocytic pathway presented with class II MHC molecules

Intracellular proteins are degraded into short peptides by a proteasome (a cylindrical particle with a central channel)

Degradation of protein occur within the central hollow of the proteasome

Endogenous antigens: the cytosolic pathway

Endoplasmic reticulum (ER)

Cytosol

Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I

Newly synthesisedMHC class I molecules

Peptides needaccess to the ER in

order to be loaded onto MHC class I molecules

ER membrane

Lumen of ER

Cytosol

Transporters associated withantigen processing (TAP1 & 2)

peptides are translocated by TAP into the ER

TAP is optimized to transport peptides that will interact with class I MHC

TAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

Peptide

ER membrane

Lumen of ER

Cytosol

TAP-1 TAP-2

Peptide

ATP-binding cassette(ABC) domain

Hydrophobictransmembranedomain

Peptide antigensfrom proteasome

Endoplasmic reticulum

Calnexin bindsto nascent

class I chainuntil 2-M binds

TAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

TAP-1 TAP-2

PeptideTAP-1 TAP-2

Peptide

B2-M binds and stabilises

floppy MHC

Tapasin, calreticulin, TAP form a complex with the

floppy MHC

Peptides are loaded onto the MHC molecule

and the structure becomes compact

Peptides assemble with class I MHC aided by chaperone molecules

Fate of MHC class I

Sent to lysosomes for degradation

Exported to the cell surface

Cytoplasm

ER

Cell surface

calnexin

Golgi

Endogenous antigenpeptide

Endogenous antigens: the cytosolic pathway

Proteases produce 13~18 amino acid long peptides from antigens

Endosomes

Exogenous antigens: the endocytic pathway

Increasein acidity

Cell surface

Uptakedegraded into peptides

proteases are activated by the decrease in pH

prevent any endogenously derived peptides from binding

to class II molecules

invariant chain (Ii chain) interacts with the peptide-binding cleft of the class II molecules

In the endoplasmic reticulum

MHC class II maturation and invariant chain

Endosomes

Cell surface

Uptake

MHC class II compartment (M II C)

Ii complex exit from the ERa short fragment of the Ii chain termed class II associated invariant chain peptide (CLIP) occupies th

e peptide-binding groove

Removal of CLIP

?

How can the peptide bind to the peptide-binding groove of class II molecules?

HLA-DM is required to catalyze the exchange of CLIP with antigenic peptides

M II C

HLA-DM

Surface expression of MHC class II-peptide complexes

Transported to the cell surface

Sent to lysosomes for degradation

Exogenous antigens: the endocytic pathway

Which cells can present antigen to CD8+ T cells? And Why?

All nucleated cells Which cells can present antigen to CD4+

T Cells? And Why? Professional antigen presenting cells

Dendritic CellsMacrophagesB cells

Professional APCs are distinguished by two properties: express class II MHC molecules on their membranesdeliver a co-stimulatory signal that is necessary for CD4 T cell activation

Nonprofessional APCs: be induced to express class II MHC molecules or a co-stimulatory signal function in antigen presentation only for short periods

of time during a sustained inflammatory response

Antigen presenting cell (APC)

Classification of APC

Dendritic cells are the most effective of APCs constitutively express a high level of class II MHC mole

cules and costimulatory activity activate naive CD4 T cells

Macrophages must be activated before they express class II MHC molecules or the co-stimulatory molecules

B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory molecules

Dendritic cell (DC)

acquire their name because of the numerous long membrane extension similar to the dendrites of neurons

Immature vs. Mature DCs

Immature DCs express TLR, FcR, C3bR, and class I and II MHC I/II molecules. They are good at antigen uptaking and processing, but poor at inducing T cell activation.

Mature DCs are derived from immature DCs upon stimulation by TLR signals and various cytokines, expressing high levels of co-stimulatory molecules. While losing antigen capturing capacity, they are stronger inducers of T activation.

DCs in non-lymphoid tissues

Interstitial DCIdentified in all tissues other than the brain

Langerhans CellFound in the epidermal layers of the skin

Both are particularly good at antigen capturing

Name by Tissue Distribution

DCs in lymphoid tissues

Interdigitating DC （ IDC）Mainly found in T cell area in lymphoid tissuesExpressing high levels of class II MHC and co-stimulatory moleculesParticularly potent in T cell activation

Follicular DC (FDC)Mainly found in lymphoid folliculesExpressing high levels of Fc receptor and complement receptorCritical in germinal center reactiondo not function as antigen presenting cells

Name by Tissue Distribution

What to remember

The two major pathways for antigen presentation

The features of three major types of professional APCs

Study question

Define the following terms: Exogenous antigen -is produced outside of the host cell Endogenous antigen -is produced within the host cell itself

CD4 Th cells recognize antigen with class (II) MHC molecules on (antigen-processing) cells.

CD8 TC cells recognize antigen with class (I) MHC molecules on (target) cells.

(Endogenous) antigens are degraded into peptides within the cytosol by (proteasomes) and assemble with class (I) molecules in the RER.

Study question

Study question

Cells that can present antigen to TH cells have been classified into two groups—(professional) and (nonprofessional) APCs.

(Dendritic cells) are the most effective of APCs

Study question Fill in the blanks in the following statements with the most approp

riate terms:a. ( ), ( ) and ( ) all function as professional antigen presenting

cells.b. Only antigen-presenting cells express class ( ) MHC molecules,

whereas nearly all cells express class ( ) MHC molecules.c. ( ) antigens are internalized by antigen-presenting cells, degrad

ed in the ( ), and displayed with class ( ) MHC molecules on the cell surface.

d. ( ) antigens are produced in altered self-cells, degraded in the ( ), and displayed with class ( ) MHC molecules on the cell surface.