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.