1. （Antigen Processing and Presentation）
抗 原 加 工 提 呈
（Antigen Processing and Presentation）
张 勇
上海交通大学医学院免疫学教研室

2. T cells do not recognize native antigensY B T
Proliferation and antibody production
No proliferation
Cross-linking of surface membrane Ig
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3. Y Antigens must be processed in order to be recognized by T cells T
native Ag
Cell surface
native Ag
Soluble
peptides
of Ag
Cell surface
peptides
of Ag
Cell surface peptides of Ag presented by cells that express MHC antigens
Ag processing and presentation
No T cell
response
No T cell
response
No T cell
response
No T cell
response
T cell
response
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4. Since all cells expressing either class I
or class II MHC molecules can present peptides to T cells, strictly speaking they all could be designated as Antigen Presenting Cells (APC).
However,………………..
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5. Cells that display peptides associated with
Target cells:
Cells that display peptides associated with
class I MHC molecules to CD8+ Tc cells
are referred to as target cells.
Professional antigen presenting cells (APC):
class II MHC molecules to CD4+ Th cells
are called APC.
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6. APCs: highly specialized cells  Uptake and process antigens
 Express co-stimulatory molecules ( B7 )
 Express class II MHC molecules
 Present antigenic peptide to CD4+ T-cell
the main APCs are:
dendritic cells, macrophages and B cells.
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7. The 3 types of APCs
Constitutively express a high level of MHC II and the co-stimulatory protein,B7. the most effective APC
must be activated by the process of phagocytosis before expressing class II MHC and B7.
Constitutively express class II MHC but must be activated to produce B7.
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8. 1. dendritic cell (DC) discovered in 1973 Tissue –resident DC
Immature DC(iDC)
surface receptors recognize microbes
migrate to local lymph nodes
Within lymph nodes DC
mature DC(mDC)
present antigens to T cells in MHC molecules
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9. iDC mDC high levels of class II MHC and B7
Low levels of class II MHC and B7
Strongly internalize antigens but have no presentation ability
high levels of class II MHC and B7
Strongly present antigens but can’t uptake antigens
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10. 2. macrophage( M)
monocyte：blood
macrophage：tissue
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11. CR and FcR specialized to internalize particle antigens
receptors
mannose receptor
LPS receptor
CR and FcR specialized to internalize particle antigens
MHC and co-stimulatory molecules
class Ⅱ MHC：inducible expressed after phagocytosis
B7：inducible expressed after phagocytosis
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12. 3. B lymphocyte BCR (smIg): take up soluble antigens efficintly
Constitutively express class Ⅱ MHC
Inducible expression of B7
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13. The properties of various APCs
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14. Antigen processing and presentation
protein antigen is degraded into peptide
antigen presentation
association of peptide with MHC and
transportation of MHC-peptide complex to the
cell membrane
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15. Examples: viral proteins, tumor antigens
endogenous antigens：proteins that are synthesized within the cytoplasm of the cell.
Examples: viral proteins, tumor antigens
exogenous antigens：antigens originate outside the cell Examples: bacteria proteins
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16. Processing and Presentation of Endogenous Antigens
(MHC class I pathway)
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17. Degradation in the proteasome
Cytoplasmic cellular proteins, including non-self proteins
are degraded continuously by a multicatalytic protease of 28 subunits
The components of the proteasome include MECL-1, LMP2, LMP7
LMP2 & 7 encoded in the MHC
Proteasome cleaves proteins after hydrophobic and releases peptides into the cytoplasm
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18. ENDOPLASMIC RETICULUM
Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I
ENDOPLASMIC RETICULUM
Newly synthesized
MHC class I molecules
Peptides need
access to the ER in
order to be loaded onto MHC class I molecules
CYTOSOL
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19. Transporters associated with antigen processing (TAP1 & 2)
ER membrane
Lumen of ER
Cytosol
ER membrane
Lumen of ER
Cytosol
ATP-binding cassette
(ABC) domain
Hydrophobic
transmembrane
domain
Peptide antigens
from proteasome
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
Transporter has preference for >8 amino acid peptides
with hydrophobic C termini.
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20. Maturation and loading of MHC class I
Endoplasmic reticulum
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
TAP-1
TAP-2
Peptide
Calnexin binds
to nascent
class I chain
until 2-m binds
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
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21. Fate of MHC class I Exported to the cell surface
Sent to lysosomes for degradation
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22. The presentation of Class I MHC/ peptide by a target cell to a CD8+ Tc cell results in the proliferation and subsequent differentiation of a Tc into a killer/effector cell. The Tc can then participate in TARGET CELL KILLING.
Target cell
“kiss of dead”
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23. 上海交通大学医学院免疫学教研室

24. Processing and Presentation of Exogenous Antigens
(MHC class II pathway)
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25. Uptake of exogenous antigens
Membrane Ig
receptor mediated
uptake Y Y
Phagocytosis
Complement receptor
mediated phagocytosis Y
Pinocytosis Y
Fc receptor mediated phagocytosis
Uptake mechanisms direct antigen into intracellular vesicles
for exogenous antigen processing
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26. Exogenous pathway Cell surface Protein antigens Uptake In endosome
Increase
in acidity
Protein antigens
In endosome
Endosomes
To lysosomes
Cathepsin B, D and L proteases are activated by the decrease in pH
Proteases produce 15~30 amino acids long peptides from antigens
上海交通大学医学院免疫学教研室

27. MHC class II maturation and invariant chain
In the endoplasmic reticulum
Invariant chain stabilises MHC class II by non- covalently binding to the immature MHC class II molecule and forming a nonomeric complex
Need to prevent newly synthesised, unfolded self proteins from binding to immature MHC
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28. Class II associated invariant chain peptide (CLIP)
Cell surface
Uptake
Endosomes
(Ii)3 complexes
directed towards
endosomes by
invariant chain
Cathepsin L degrades Invariant chain
CLIP blocks groove in MHC molecule
MHC Class II
containing vesicles
fuse with antigen
上海交通大学医学院免疫学教研室

29. Removal of CLIP ?
How can the peptide stably bind to a floppy binding site?
Competition between large number of peptides
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30. HLA-DM catalyses the removal of CLIP
MIIC compartment
HLA-DM
Replaces CLIP with a peptide antigen using a catalytic mechanism
Sequence in cytoplasmic tail retains HLA-DM in endosomes
HLA-DM
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31. Surface expression of MHC class II-
peptide complexes
Exported to the cell surface (t1/2 = 50hr)
Sent to lysosomes for degradation
MIIC compartment sorts peptide-MHC complexes for surface expression or
lysosomal degradation
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32. The result of Class II MHC/peptide by an APC to a CD4+ Th cell is: ACTIVATION and PROLIFERATION of the Th cell and then “help” other immuno-cells to activate.
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33. 上海交通大学医学院免疫学教研室

34. Separate antigen-presenting pathways are utilized for endogenous (green) and exogenous (red) antigens. The mode of antigen entry into cells and the site of antigen processing determine whether antigenic peptides associate with class I MHC molecules in the rough endoplasmic reticulum or with class II molecules in endocytic compartments.
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35. 内源性和外源性抗原加工途径特点比较
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36. 本章要求： 1.掌握APC的概念、种类及生物学功能。 2.掌握内源性和外源性抗原加工提呈的过程。 3.掌握下列常用名词：
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