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Summary Of The Last Section
Types of pathogens & antigens Cytosolic – “endogenous” Endocytic/vesicular – “exogenous”
Two classical pathways for Ag processing Endogenous MHC Class I pathway CD8+ T cells Exogenous MHC Class II pathway CD4+ T cells
Ag processing, presentation & clinical relevance MHC deficiencies Mechanisms used by pathogens to evade host immunity Considerations in vaccine design
Cell interactions & co-operation Lymphocyte re-circulation & homing Cell interactions: membrane-bound & soluble molecules
Dendritic cells (DC)& the initiation of immune responses
• Lymphocyte activation– Ag recognition (Signal 1)– Co-stimulations (Signal 2)
• T-B cell cooperation– The original model– The modified model– The contemporary model
• DC – the TRUE professional APC– Activator of naïve T cells– Special Ag processing machine– Ag cross-presentation
• Immune initiation & the ‘Danger model’
Ag recognition alone (signal 1)does not initiate an immune response
“signal 2” is needed
Question 1: How is an (adaptive) immune response initiated?
• Importance of thymus in immune responses– Miller & Good (1961)
• Phenomenon of T-B cell co-operation– AJS Davies (1964)– Claman & Mitchell (1967)
• ‘Linked recognition’ – the ‘hapten-carrier effect’– N. A. Mitchison (1970)
T-B cell cooperation
The “original” 2-signal model(Bretscher & cohn, 1970)
THB
2nd signal (‘co-stimulation’)
(1)
(2)
Activated
Finding:
T cell Ag recognition is MHC-restricted
Question 2
How could T and B cells recognize the same Ag if T cells recognized only processed Ag presented by MHC?
Linked recognition - the ‘carrier-priming’ experiment (N. A. Mitchison)
TNP-C1
C2
TNP-C2B
TH
Anti-TNP response
TNP: A hapten of trinitrophenyl group
The “modified” model
TH B
Cytokines etc.
(1)
(2)
Activated
TNP
C2
Another problem:
Resting B cells do not activate naïve T cells
Question 3
How can naive T cells be activated?
• Naïve lymphocytes Cells that have never encountered specific antigen
• Armed effector lymphocytesActivated & differentiated cells that may respond to antigen binding alone to produce effector functions
• Memory lymphocytesCells that have experienced specific antigen previously but need to be triggered to differentiate again to become effector cells
Dendritic cell (DC)
- The activator of naïve T cells
R. M. Steinman
(Rockefeller)
Photograph copyright:G.G. MacPherson (Oxford, 1997)
Dendritic cells & follicular dendritic cells are two very different cell types
DC FDC
Origin: Bone marrow-derived ?Haematopoietic
Where: T areas, B follicles& peripheral tissues
Nature: endocytic & migratory resident
Life-span: days years
Present Ag: as peptide to T cells as IC to B cellsby MHC by Ig-Fc
DC Biology
• Sentinel (constant surveillance)– Distribution throughout peripheral tissues
• Endocytic (Ag uptake)– Phagocytosis– Micropinocytosis– Macropinocytosis
• Migratory (Ag transport)– from peripheral tissues to secondary lymphoid organs
AL: Afferent LymphaticsSCS: Subcapsular SinusPCV: Post-Capillary Venule(HEV: High Endothelial Venule)
The site of lymphocyte activation
+ DC
GC
(B + FDC)F
T: T cell areaB: B cell area
F: B cell follicleGC: germinal centre
Organizeddistribution
DC: An unique Ag processing machine
(immature DC)
• Attenuated lysosomal potential for Ag degradation– Ag sequestered from lysosome for extended period
• Regulated cathepsin S activity– delayed cleavage of MHC II-associated Ii chain favouring MHC II
transport to lysosome
(Mellman I & Steinman RM, Cell. 2001; 106:255-8)
The invariant chain
CLIP
Ii
Two CLASSICAL pathwaysfor Ag processing
• “MHC class I pathway” CD8+ T cells (Endogenous/cytosolic/TAP-dependent pathway)
• “MHC class II pathway” CD4+ T cells(Exogenous/endocytic/TAP-independent pathway)
Ag ‘cross-presentation’ - DC breaking the rules
• Ag “cross-presentation”:– Endocytic/exogenous Ag Class I pathway (TC)
(proteasomal proteolysis, TAP-dependent)
• “Indirect” Ag presentation:– Cytosolic/endogenous Ags Class II pathway (TH)
Cytosolic/Endogenous Ag
Endocytic/Exogenous Ag
CD8+ T
MHC Class I
CD4+ T
MHC Class II
Cross-presentation Indirect presentation
Prot
easo
me
(TAP
-dep
ende
nt)
Lyso
som
e
CRAIG RR. Nature 425, 351-52 (2003)
Antigens cross-presented
• Virus-infected apoptotic cells
• Apoptotic tumor cells
• Other cell death due to normal cell turnover
• Transplantation Ags
• Endocytosed Ag: small fragments (3-12 KD)
DC – the TRUE professional APC
• Sentinel position• Endocytic• Migratory
• Unique location in the secondary lymphoid organs• Special Ag processing machine
• High MHC Class I, Class II (Ag presentation)• Constitutive expression of B7 (co-stimulation)
Co-stimulations- cell interactions other than Ag specific stimulation
Adhesion molecules
Cytokines & cytokine receptors
B7/CD28, CTLA-4:
-B7:CD28 interaction delivers a positive signal to T cells- B7:CTLA-4 interaction delivers a negative signal to T cells
CD40/CD40L:
- crucial for B cell growth & differentiation
The contemporary model
Naïve TH
Cytokines etc
(1)
(2)
DC
Activated
(1)(2)
CD28
B7Co-stimulations
B
T-B cell cooperation
Effector TH B
CD40L:CD40
(1)(2)
Abs:IgMIgG1, IgEIgAIgG2a, IgG3(isotype switch)
Cytokines:IL-4IL-5IFNg
Further questions:
Do DCs need to be activated?Do DCs need to be activated?
What then activates DCs?What then activates DCs?
Vaccination: why adjuvant?Vaccination: why adjuvant?
Immune system turned on Immune system turned on by “non-self” or by “Danger” ?by “non-self” or by “Danger” ?
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