Transcript APC & Antigen presentation

APC & Antigen presentation
antigen-presenting cell,
APC
Concept
A group of immune cells, whose role
is to take up, process and present
antigenic peptides to T cells.
• Professional APC
– Macrophages, dendritic cells, and B cells, which
can express MHC class II molecules.
• Non-professional APC
– Other cell type capable of expressing MHC
class II molecules
eg. Endothelial cells, EC
Fibroblasts
Activated T cell
1 Dendritic cell，DC
• highly branched
morphology
• can active naive T
cells
• markers
1) Markers
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CD1a, CD11c, CD83
Pathogen receptor, FcR
MHC II
co-stimulating factors (CD80,CD86)
Adhesion molecular CD40
CD54 (ICAM-1), etc.
• secreting cytokines
– IL1, IL-6, IL-12, TNF-a, IFN-a,
chemokines
2) Source, distribution and classification
• Source
DC are bone marrow-derived
– Myeloid DC
– Lymphoid DC
Bone marrow
Blood
Blood
dendritic cell
Tissue
Dendritic cell
?
Pluripotent
stem cell
Mycloid
precursor
Monocyte
Indeterminate
cell
Macrphage
• Distribution and classification
DCs are found in many organs throughout the
body
– DC in lymphoid tissue
• Interdigitating cell, IDC
• Follicular DC, FDC
• thymic dendritic cell, TDC
– DC not in lymphoid tissue
• Langerhans cells
• Interstitial DC
– DC in body fluid
• Veiled cells
• Peripheral blood DC
interdigitating DC, IDC
IDC express high levels of MHC molecules, and are
more potent antigen-presenting cells than others.
follicular DC, FDC
FDC
B cells
FDC express high levels of membrane receptors for
antibody and complement. By these, FDC actives the B
cells in lymph nodes.
Langerhan’s cells, LC
Langerhans cells found in the epidermis (skin) and mucous
membranes (left), expressing high levels of FcR, receptor of
complement, and MHC. Birbeck granule is the characteristic
organelle. After capturing antigen in the tissues by phagocytosis or
by endocytosis. DC migrate into the blood or lymph and circulate to
lymphoid organs, become IDC（right）。
Cell
MHC-II
FcR
C3bR Birbeck
FDC
IDC
TDC
LC
Interstitial DC
VC
M
BL
++/-++++(I,II)
++
++++(I,II)
++++
+++
++/-++
+
-+
+
?
?
+
+
+
-?
+
?
?
+
+
--+
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+
----
3) Differentiation, development,
maturing and migration
• Lymphoid DC
– DC in lymph, negative selection of T
cells
• myeloid DC
– Immature
– mature
• Four phases
– Pre-DC
• Monocyte, Mo
– Immature DC
• Uptake antigen
• Express MHC
• Secrete chemokines
– Migration
– Mature DC
• Express high levels of MHC I and II,
CD80, CD86, CD40, CD54, HSP, etc.
4) activation and tolerance
• Activation
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First signal (MHC-peptide)
Second signal (co-stimulating factors)
Adhesion molecular
Cytokines (IL-12)
• Tolerance
– Negative selection
2 Mononuclear
phagocyte system, MPS
Macrophages (M) are phagocytic
cells of monocytic lineage residing
within tissues and are particularly
well equipped for effective antigen
presentation.
Different names in different tissues
• Monocyte ( blood )
• Kupffer cells ( liver )
• Mesangial cells ( kidney glomerulus )
• Microglia ( brain )
• Alveolar macrophages ( lung )
• Histiocyte ( connective tissue )
The process of M activation
3
抑制免疫功能
suppressor M
1
rested M
2
responsive M
PGE
stimulated M
activated M
LFA-1
过度活化
适度活化
signal
病原体
细胞增生
趋化，杀菌
MHC-II
First signal:
MAF/IFN-,
MSF
提呈Ag，
激活LC，
结合TC，
杀瘤，杀菌
second signal:
LPS/IFN-,
MSF,CK,
• markers
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MHC II
CR1（CD35）
CR3（CD11b/CD18）
IgG Fc受体
• Functions
– Receptors
– Enzymes
– Cytokines
扫描电镜显示，在感染早期，M伸出长长的
伪足去捕获细菌
Biologic effects of M
3 B cell
bone marrow-dependent lymphocyte
About 5-15% of the circulating lymphoid pool are
B cells difined by the presence of surface
immunoglobulin.
Markers of B cells
Characteristics of B cells
– not actively phagocytic
– Class II-positive
– BCR
Antigen-presenting cells
APC
Present to
Macrophage
T cell via MHC antigen
Dendritic cells
T cell via MHC antigen
B cells
T cell via antigen captrue by
surface antibody and MHC
antigen
T cell via MHC antigen
Activated T cells
ANTIGEN PROCESSING
AND PRESENTATION
1. Binding and uptake of antigen
–
depends on the physical state of the
antigen and the cell type involved.
2. Antigen processing
–
–
MHC class I processing pathway
MHC class II processing pathway
3. Antigen presentation
1 Binding and uptake of antigen
• exogenous antigens
– Bacteria, cells and soluble proteins
– processed by APC
• endogenous antigens
– Produced within the cells, Such as
viral proteins or tumor proteins
– processed by host cell
Uptake antigen by immature DC
• Pinocytosis
– Liquid or small granule
• Receptor-mediated endocytosis
– effective
– selective
– saturated
• FCR, 甘露糖R
• Phagocytosis
– Large molecular or microbe
Uptake antigen by MPC
• Phagocytosis
– Large solid or molecular complex, such
as bacteria, fragment of cells, etc.
– Phagecyte (m, granulocyte)
• Pinocytosis
– Receptor-mediated pinocytosis
• Endocytosis
– Low levels of particulate or soluble
antigens
– exocytosis
Uptake antigen by B cells
• nonspecifically engulfed
• BCR-mediated
2 Antigen processing
• Degradation of externally- or
internally- derived antigen into
short peptide sequences
• Association of the peptide with
MHC molecules
Two antigen-processing pathways
MHC class I
MHC class II
Major antigen
sources
Processing
machinery
Cell type where
active
Site of antigenMHC binding
MHC utilized
endogenous
antigen
proteasome
exogenous antigen
endoplasmic
reticulum
lysosome and
endosome
MHC class I
MHC class II
Presents to
CD8+ T cell (Tc)
CD4+ T cells (Th)
lysosomal
enzymes
all nucleated cells professional APCs
MHC class I processing
pathway
MHC class I processing
pathway
Antigenic protein proteosome peptide
fragment released into cytosol binds to
TAP protein moves to endoplasmic
reticulum(ER)
Newly synthesized Class I a chain and b2
microglobulin move to ER calnexin binds
to a chain peptide fragment and b2m bind
to a chain release of a chain from
calnexin complex moves to Golgi apparatus
glycosylation in Golgi apparatus secretory
vesicle plasma membrane
Structure of MHC class I
proteasome
• LMP,
low molecular weight polypeptide
or large multifunctional protease
• Structure:
– 20S
26S
• Function:
– Degradation of protein
26S protease cmplex
20S proteasome
twin 19S cops
TAP, transporter associated
with antigen processing
• structure:
– TAP-1 and TAP-2
• function:
– transports small peptides (8-13 aa) to
the ER
calnexin
• Structure
– 88kD integral ER membrane chaperone
protein
• Function
– Binds to a nascent MHC class I a chain
after release from a ribosome into the
ER lumen so that the a chain will not
leave the ER until it binds both a short
peptide sequence and b2 microgobulin
Molecular chaperones: calnexin,
calreticulin,tapasin
MHC class II processing
pathway
MHC class II processing
pathway
• Antigenic protein endosome/lysosome
peptide fragment
• Newly synthesized class II molecules
move to ER and associate with invariant
chain protein molecule move to Golgi
apparatus move to endosomes/lysosomes
release of invariant chain from class II
molecule class II binds antigenic peptide
fragment transport to cell surface
Structure of MHC class II
Endosome & lysosome
• acidic protease & lysosome enzymes
• Function
– Degrade protein into peptide fragments
(10-30 aa)
invariant chain, Ii
• Function
– Promote the formation of MHC II a b
dimer
– Directs the movement of newly synthesized
class II molecules into the Golgi and then
the late endocytic compartment of the cell
– Prevent the binding of antigenic peptides to
class II molecules, at least until the class
II molecule reaches the late endocytic
compartment
• CLIP, class II associated invariant chain
peptides
3 Antigen presentation
• Antigen presentation
– The activation of T cells via T cell
receptors, which specifically recognize
antigenic peptide in association with
either MHC class I or II molecules on
the surface of APC.