?11? ???????? Antigen Processing

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?11? ????????Antigen Processing Presentation
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T cells do not recognise native antigens
Y
Y
Y
Y
Y
Y
Cross-linking of surface membrane Ig
Proliferation and antibody production
No proliferation No cytokine release
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Antigens must be processed in order to be
recognised by T cells
ANTIGEN PROCESSING
T cell response
No T cell response
No T cell response
No T cell response
No T cell response
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MHC directs the response of T cells to foreign
antigens
MHC antigens PRESENT foreign antigens to T
cells Cells that present antigen are ANTIGEN
PRESENTING CELLS
Ag
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Ag
B??
???
Ab
APC
Th??
Ag?-MHC??
T??
Tc??
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Contents

• ??????
• ????????

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??? ??????Antigen Presenting Cells

• ????
• ??????

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??????

• ???????
• (Antigen processing and presentation)
• ?????????????????????MHC????????
• ??????MHC????????,??????????T????????

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• ?????
• (endogenous antigens)
• ????????????
• ????????????
• ??????????????????
• ??????????????,?????
• ???????,?MHC?????

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• ?????
• (exogenous antigens)
• ???????????????
• ?????????????
• ??????????????
• ???????
• ?????????,?MHC?????

Listeria
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????????

• ??????
• (antigen presenting cell,APC)
• ??????????????Ag??????????????(T??)???????????????
  ????????B???

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• ??APC
• ??????
• ??MHC????
• ??APC(professional APC)
• MF,DC,B???
• ??MHC????
• ??APC(non-professional APC)
• ????,????,???T???
• ?????????MHC-????

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(No Transcript)
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1??????(dendritic cell, DC)

• ???????
• ?????APC

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DC??

• ????
• ???DC
• ??DC (FDC)
• ??DC(CD11c)
• ?????? (LC)
• ???DC (IDC)

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??? ????
B??

• ???????

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???DC???DC

• ???DC(Immature DC)
• ??????????????????????
• ??????????????
• ??(??)
• ??????
• ???
• ??????MHC??????????????

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• ??????????
• ????????,?????????????
• ??????,?????-MHC???
• ???????????????
• ??DC(Mature DC)
• ???,?????????
• ???MHC??????????????
• ?????????

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• ??????LC
• ????????????????T???,??IDC

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2?????(Macrophage, Mf)
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?????

• ?????(??)
• ????(??)
• ????(????)

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• ????????,???(?,????)
• ??????????????????????????(?)
• ???????????????????(?)

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??

• ???????
• ??????,?????????
• ?????????

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MF??????

• ????
• ??
• ??
• ??????

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• ??????
• (pattern recognition receptors,PRR)

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3?B??
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B????????

• ?????????
• BCR????
• ???
• ???

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??? ????????Antigen Processing and
Presentation Pathways

• MHC????
• MHC????
• ?????

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??

• T????????????Ag,
• ????TCR??Ag?-MHC?????
• CD4T---Ag?-MHC??????
• CD8T---Ag?-MHC??????

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The site of pathogen replication or mechanism of
antigen uptake determines the antigen processing
pathway used
EXTRACELLULAR OR ENDOSOMAL REPLICATION
Y
Vesicular Compartment Contiguous with
extracellular fluid Exogenous processing (Streptoc
occal, Mycobacterial antigens)
INTRACELLULAR REPLICATION
Cytosolic compartment Endogenous
processing (Viral antigens)
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Antigens generated by endogenous and exogenous
antigen processing activate different effector
functions
EXOGENOUS PATHOGENS
Y
ENDOGENOUS PATHOGENS
Eliminated by Antibodies and phagocyte activation
by T helper cells that use antigens generated
by EXOGENOUS PROCESSING
Eliminated by Killing of infected cells by CTL
that use antigens generated by ENDOGENOUS
PROCESSING
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?????????????

• Exogenous processing and presentation pathway
• MHC class ? pathway
• ???Ag?MHC??????

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• ??
• ???????????
• MHC??????????
• MHC??????
• ???CD4T??

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1??????????????

• Uptake and degradation of exogenous antigens
• APC???????Ag,????
• ????????????/???
• Ag???????Ag?
• ??????(compartments)

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APC???????Ag,????
Membrane Ig receptor mediated uptake
Y
Phagocytosis
Complement receptor mediated phagocytosis
Pinocytosis
Fc receptor mediated phagocytosis
Uptake of exogenous antigens
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Exogenous pathway
Protein antigens In endosome
Cathepsin B, D and L proteases are activated by
the decrease in pH
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(No Transcript)
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2?MHC??????????

• Biosynthesis and transportation of MHC class?
  molecules
• ??????MHC??????
• ?Ii???? (aßIi)3???

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MHC class II maturation and invariant chain
In the Endoplasmic Reticulum
Need to prevent newly synthesised, self proteins
from binding to immature MHC
Invariant chain stabilises MHC class II by
binding to the immature MHC class II molecule
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Conception

• ?i?
• ?a-associated invariant chain,?a????????
• ???????????
• ???????ER????????????????
• ??????????

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Structure of invariant chain
Three extended peptides each bind into the
grooves of three MHC class II molecules to form
the nonomeric complex
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CLIP of invariant chain
CLass II associated Invariant chain Peptide
(CLIP) A peptide of the invariant chain blocks
the MHC molecule binding site
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Conception

• CLIP
• Class ?-associated invariant chain peptide
  ,????????????
• ?i??81??104???????????
• ????MHC????????????

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3?MHC??????

• Peptide-loading of MHC class ? molecules
• ?i????????????(M?C)
• ?i???,???????????CLIP
• HLA-DM??,CLIP???????
• HLA-DM??,????????????
• Ag?-MHC??????

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Class II associated invariant chain peptide (CLIP)
MHC Class II containing vesicles fuse with
antigen containing vesicles
(??Ii)3 complexes directed towards endosomes
by invariant chain
Cathepsin L degrades Invariant chain CLIP blocks
groove in MHC molecule
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Removal of CLIP
?
How can the peptide stably bind to a floppy
binding site?
Competition between large number of peptides
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HLA-DM catalyses the removal of CLIP
MIIC compartment
HLA-DM Replaces CLIP with a peptide antigen using
a catalytic mechanism
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Conception

• M?C
• MHC class ? compartment,MHC??????
• ????????? MHC?????HLA-DM??pH??????
• MHC??????????

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• HLA-DM?????
• HLA-DM???????????????? ?????,????????????? ???,??
  ??????,?????? ????????
• HLA???????????HLA-DM??? ??,??????????????? ?????

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4????CD4T??

• Presentation of exogenous antigen
• Ag?-????????????APC??
• ?CD4T????

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Surface expression of MHC class II- peptide
complexes
MIIC compartment sorts peptide-MHC complexes for
surface expression or lysosomal degradation
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?????????????

• Endogenous processing and presentation pathway
• MHC class ? pathway
• ???Ag????MHC??????

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• ??
• ???Ag???????
• MHC??????
• ???CD8T??

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1??????????

• Generation of endogenous antigenic peptide
• ????????
• ?????(LMP)?????

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Degradation in the proteasome
Cytoplasmic cellular proteins, including non-self
proteins are degraded continuously by a
multicatalytic protease of 28 subunits
These components are induced by IFN-? and replace
constitutive components to confer proteolytic
properties The components of the proteasome
include MECL-1, LMP2, LMP7 LMP2 7 encoded in
the MHC Proteasome cleaves proteins into
hydrophobic and basic amino acids
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2?????????????

• Transportation of endogenous antigenic peptide
  into ER
• ??????????(TAP)???ER

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Peptide antigens produced in the cytoplasm are
physically separated from newly formed MHC class I
ER
CYTOSOL
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Transporters associated with antigen processing
(TAP1 2)
Transporter has preference for 8-15 amino acid
peptides with hydrophobic, basic C termini
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3?MHC??????

• Peptide-loading of MHC class ? molecules
• ???????????????? MHC??????
• tapasin???MHC?????TAP???????
• Ag?-MHC?????????

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Maturation and loading of MHC class I
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
Calnexin binds to nascent class I chain until
ß2-M binds
ß2-M binds and stabilises floppy MHC
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4????CD8T??

• Presentation of endogenous antigen
• Ag?-MHC?????????
• ?????????????
• ?CD8T????

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Fate of MHC class I
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Evasion of immunity by interference with
endogenous antigen processing
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Evasion of immunity by interference
with endogenous antigen processing
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?????????????

• Non classical pathway
• ????????MHC??????
• ??????????????
• ??????????????
• ----?????????????CD8T??
• ????????MHC??????
• ???????????,???/?????
• ----?????????????CD4T??

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• ????(cross-priming)
• ???APC ????????????????CD8T?????
• DC????????

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• ????????????????,
• ???????????????????????????