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Basic Immunology - Pécsi Tudományegyetemimmbio.aok.pte.hu/hu/oktatas_new/eloadasok_2011/... ·...
Transcript of Basic Immunology - Pécsi Tudományegyetemimmbio.aok.pte.hu/hu/oktatas_new/eloadasok_2011/... ·...
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Basic Immunology Initial phase of the immune response:
eary T-B cell activation and cooperation, CD3 complex and signaling, BCR signaling.
Costimulation. T-dependent, T-independent antigens
Ferenc Boldizsár
03.22.2012.
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Adaptive immune response
Cellular Humoral
Innate immunity
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Main stages of the adaptive immune response
Antigen recognition
Activation, differentiation
Effector functions
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Antigen transport to the secondary lymphoid organs DCs – 1. periphery, ag take-up, processing 2. migration to T-dependent areas of secondary lymphoid organs (through afferent lymphatics) 3. ag presented on MHC-II to T cells in secondary lymphoid organs (lymph nodes, spleen) Native ag – lymph drainage to local lymph node or blood
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Immature DC
Phagocytosis
Mature DC T cell activation (B7)
Phagocytosis stops
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T cell activation
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Adhesion
Recognition
T cell
Costimulation
The first antigen recongnition encounter of naïve T cells with the
APC is called „priming”.
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2 signals are necessary for T cell activation
1. signal: TCR-CD3 complex Antigen-specific 2. signal: costimulatory signal CD28 - B7 interaction Not antigen specific
T cell differentiation and proliferation
Effector and memory T cells
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SMAC=supramolecular activation complex • Central (c) - TcR complex, CD4, CD28
• Peripheral (p) - adhesion molecules eg. LFA-1
• CD45 exclusion
The immunological synapse (A. Kupfer, M. Dustin) =activation interface between the T cell and APC
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The immunological synapse
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Lipid rafts=cholesterol&sfingolipid containing membrane microdomains - more “rigid”, than other membrane regions → provide optimal platform for the immunoreceptor signaling molecules (10-200nm)
TcR/BcR/FcεR complex
CD45
Lipid raft
1. Resting cell - antigen recognition receptors outside of rafts
2. Antigen binding→ receptor oligomerization→raft association
3. Raft clustering - development of the immunological synapse
Cytoskeleton rearrangement
M. Dykstra, A. Cherukuri, S.K. Pierce: Rafts and synapses in the spatial organization of immune cell signaling receptors J. Leukoc. Biol. 70: 699-707; 2001."
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Receptor Resting cell Activated cell TcR Lck, Fyn ZAP-70
LAT, Cbl SLP-76 CD4, CD8 PLCγ PKA, PKC Vav, Grb2
BcR Lyn Syk, Vav
PLCγ
Lipid raft associated signaling molecules
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TcR signaling - early steps
J Lin, A Weiss: Proximal tyrosine kinases that initiate T cell activation
ITAM= immunoreceptor tyrosine-based activation motif
1. After TcR cross linking coreceptors (CD4, CD3, CD45) associate to TcR 2. Protein tirosine kinase (PTK) Lck and Fyn activation: CD45 phosphatase removes an
inhibitory phosphate 3. Fyn and Lck phosphorylates ITAMs of the CD3 complex 4. ZAP-70 PTK “docks” to the phosphorylated ITAMS of the ζ-chain and phosphorylates
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1. Antigen recognition
2. PTK activation
3. Ca2+ signal
4. Protein phosphorylation
5. Translocation of transcription factors
6. Gene activation
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Activation
Fyn, Lck, ZAP-70 Gene expression changes
Kinetics of T cell activation
Resting lymphocyte
PTK activation
Ca2+-signal
Protein phosphorylation
RNA synthesis
Protein synthesis
DNA synthesis
Lympho- blast
lymphocytes
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Autocrine IL-2 effect - CD25 (IL-2Rα chain)
chains:
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Role of CD28 and CTLA-4 molecules in T cell activation CD28 (naive T cell) - Activation CTLA-4 (activated T cell) - Inhibition
Therapeutic possibility: Inhibition of abnormal T cell activation in autoimmune diseases
CTLA-4-Ig (Abatacept) Rheumatoid Arthritis (RA) therapy
CTLA-4 binds B7 with higher affinity than CD28.
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Costimulatory molecules
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T cell signaling as “target”
Name Target Effect Application Anti-CD3 CD3 T cell depletion transplantation (OKT3) Anti-CD25 CD25 T cell suppression transplantation (Daclizumab) Cyclosporin A calcineurin T cell suppression transplantation Tacrolimus calcineurin T cell suppression transplantation CTLA-4-Ig B7 T cell suppression RA (Abatacept)
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B cell activation
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Steps of B cell activation
IgM +, IgD +B-cells
Antigen
T-factorsH
Proliferation and Differentiation of B-cells
I
+
Memory B-cells
IL-2IL-4IL-5
IL-2IL-4IL-5
IL-4
Antibody production of Plasma cells
IgM
IgG
IgA
IgE
IL-5TGF β
IL-4IL-6IL-2IFN γ
II IIIAntigen recognit ion
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Important cell surface molecule on B cells
B
BCR
MHCII
CD45
CD21 (CR2)
CD20CD19
CD35 (CR1)
LFA-1B7
CD40CD23
ICAM-1MHCI
CD32 (FcRII)γ
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T-helper cell-dependent B-cell activation
1. Activation: - Signal 1: BcR - Signal 2: co-receptors
2. Contact-dependent signals: (B*) B7 – CD28 (T) CD40 – CD40L (T*)
Cytokine receptor expression on B-cells
3. Signals derived from Th- dependent cytokines: IL-2, IL-4, IL-5 Proliferation and differentiation
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Raf
MAPK
GAPCD45
DAG
IP3PtdIns 4,5P2
PIP3
PI3 K
B t k
P L Cγ
Ca2+
Ca2+
PKCP K CSyk
Phosphorylierung der Transkriptionsfaktoren frühe Genexpression
SHC
SOSGrb2
Ras
BCR
β β αα
FynLynBlk
Syk
BCR
Antigen
F y nL y nB l k
NFATAP-1 mycNF-Bκ
NF-Bκ
IBκ
NF-Bκ
IBκ
NFATNFATP
P
P
P
CNCN
B cell receptor signaling
1. PTK activation
2. Ca2+ signal
3. Activation of transcription factors
4. Gene expression
Phosphorylation of transcription factors Early gene expression
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T-dependent and -independent antigens
B-cell
Cytokines
CD4TCR
CD40 CD40L
MHCII+Peptid T-cellH
2
1
B-cell
21
T-dependent (TD): • Protein antigens • Response without T cells ✖ • Affinity maturation ✔ • Isotype switch ✔ • Memory cell formation ✔
B-cell
NK-cell
IFNGM-CSF
γ
TNFIL-12
α
GM-CSF
Macrophage
2
1
TI-1 TI-2
T-independent (TI): • Polimer structure (eg. polisacharides, lipids, nucleic acids) • Spleen marginal zone • Response without T cells ✔ • Affinity maturation ✖ • Isotype switch ✖ • Memory cell formation ✖
TD
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T-dependent and -independent antigens