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Innate ImmunityIs that enough?
……………..not enough
Triggering Acquired ImmunityInnate Immune Defenses:
Invaders with low virulence are rapidly eliminatedInflammation-not foolproof & uncomfortable and damaging
To DEFEND EFFECTIVELY ……Acquired Immune System
Antigen Presentation & Role of Major Histocompatibility Complex
Course-VPP 703Course Teacher-Dr Suguna Rao Prof
Presentation By-Dr Somshekhar
Triggering Acquired Immunity….
Foreign Material-captured, processed, and presented
Antigen Processing & Presenting Cells-◦Dendritic cells◦Macrophages B cells (Minor role in Primary
Response)
Antigen Processing
g
Attracted by alarmins(damaged cells)
T cells do not recognise native antigens
YY
BYY Y Y YY
Y
BY
T
Y
T
Proliferation and antibody production
No proliferationNo cytokine release
Cross-linking of surface membrane Ig
Y
B
Y
B Y
B
Y
B
Y
B Y
B
Y
B
Cell surfacepeptidesof Ag
Antigens must be processed in orderto be recognised by T cells
YT
T cellresponse
No T cellresponse
No T cellresponse
No T cellresponse
No T cellresponse
Solublenative Ag
Cell surfacenative Ag
Soluble peptidesof Ag
Cell surface peptides of Ag presented by cells that express MHC antigens
ANTIGENPROCESSING
YThe site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used
Y
Cytosolic compartmentEndogenous processing(Viral antigens)
Vesicular CompartmentContiguous with extracellular fluidExogenous processing(Streptococcal, Mycobacterial antigens)
Distinct mechanisms of antigen generation are used to raiseT cells suited to the elimination of endogenous or exogenous pathogens
INTRACELLULAR REPLICATION
EXTRACELLULAR ORENDOSOMAL REPLICATION
Y
Eliminated by:Killing of infected cells by CTL that use antigens generated by ENDOGENOUS PROCESSING
YEliminated by:Antibodies and phagocyteactivation by T helper cells that use antigens generated byEXOGENOUS PROCESSING
Antigens generated by endogenous and exogenous antigen processing activate different effector functions
ENDOGENOUS PATHOGENS
EXOGENOUSPATHOGENS
What is MHC??????(Gorer & George Snell)
Every mammalian species pocesses a tightly linked cluster of genes-Major Histocompability Complex (MHC), whose products play role in intracellular recognition and in discrimination between self and nonself.T cells recognize antigen only when it is combined with an self MHC molecule (MHC restricted)
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Most cells can present antigen with class I MHC molecules to CD8+ Tc cells-Target cells
Cells that display peptides associated with class II MHC molecules to CD4+ TH cells-Antigen presenting cells (APCs)
Structures of MHC Class I & II
Antigen ProcessingExogenous Antigen-Endocytic or
exogenous processing pathwayClass II MHC molecules bind peptides and present to CD4+ T cells
Endogenous Antigen-Cytosolic or endogenous processing pathwayClass I MHC molecules bind peptides and present to CD8+ T cells
Y Y
Pinocytosis
Phagocytosis
Membrane Igreceptor mediateduptake
Y
Uptake of exogenous antigens
Complement receptormediated phagocytosis Y
Fc receptor mediated phagocytosis
Uptake mechanisms direct antigen into intracellular vesiclesfor exogenous antigen processing
Proteases produce ~24 amino acid long peptides from antigensDrugs that raise the pH of endosomes inhibit antigen processing
Endosomes
Exogenous pathway
Increasein acidity
Cell surface
To lysosomes
UptakeProtein antigensIn endosome
Cathepsin B, D and L proteases are activated by the decrease in pH
Need to prevent newly synthesised, unfolded self proteins from binding to immature MHC
Invariant chain stabilises MHC class II by non- covalently binding to the immature MHC class II molecule and forming a nonomeric complex
In the endoplasmic reticulum
MHC class II maturation and invariant chain
Endosomes
Cell surface
Uptake
Class II associated invariant chain peptide (CLIP)
(inv)3 complexesdirected towardsendosomes byinvariant chain
Cathepsin L degrades Invariant chainCLIP blocks groove in MHC molecule
MHC Class IIcontaining vesiclesfuse with antigencontaining vesicles
Removal of CLIP
?
How can the peptide stably bind to a floppy binding site?Competition between large number of peptides
HLA-DM catalyses the removal of CLIP
MIIC compartment
HLA-DMReplaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiometric levels)
Discovered using mutant cell lines that failed to present antigen
HLA-DO may also play a role in regulating DM
Sequence in cytoplasmic tail retains HLA-DM in endosomes
HLA-DMHLA-DR
MIIC compartment sorts peptide-MHC complexes for surface expression orlysosomal degradation
Surface expression of MHC class II-peptide complexes
Exported to the cell surface (t1/2 = 50hr)
Sent to lysosomes for degradation
ENDOPLASMIC RETICULUM
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)
Transporter has preference for >8 amino acid peptideswith hydrophobic C termini.
TAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-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 nascentclass I chainuntil 2-M binds
TAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
B2-M binds and stabilises floppy MHC
Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC
Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact
Maturation and loading of MHC class I
Fate of MHC class I
Sent to lysosomes for degradation
Exported to the cell surface
Endoplasmic reticulum
TAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTA
P-1 TAP-2
Peptide
TAP-1 TAP-2
Peptide
TAP-1 TAP-2
HSV protein blocks transportof viral peptides into ER
Sent to lysosomesfor degradation
Evasion of immunity by interference with endogenous antigen processing
Sent to lysosomes for degradation
Normally exported to the cell surface
Adenoviralproteinretains MHCclass I in the ER
Evasion of immunity by interference withendogenous antigen processing
Presentation of NON PEPTIDE antigens
T cells that express the γδ TCR that react with glycolipid antigens derived from bacteria such as Mycobacterium tuberculosis
These non protein antigens are presented by members of the CD1 family of non classical class I molecules
Genes encoding CD1 are located not within MHC
• T and B cells recognise antigen differently
• Antigen must be catabolised before T cells can recognise it
• Antigen processing generates antigenic peptides
• Exogenous antigen processing takes place in lysosomes
• Endogenous processing is non-lysosomal
• The mechanism of antigen processing depends upon the compartment in which the pathogen replicates
• Endogenous and exogenous antigen processing both involve uptake, degradation, complex formation and presentation
• Exogenous antigen processing uses invariant chain and HLA-DM
• Endogenous antigen processing uses proteasomes and peptide transporters in antigen processing
• Pathogens can evade immunity by disrupting antigen processing
Summary
Any Queries???????????????????
Hope Not…………
THANK YOU........