Transcript Generation of ligands for the T cell receptor

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’
Question 1:
How is an (adaptive) immune response initiated?
Ag recognition alone (signal 1)
does not initiate an immune response
 “signal 2” is needed
T-B cell cooperation
• 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)
The “original” 2-signal model
(Bretscher & cohn, 1970)
2nd signal (‘co-stimulation’)
(2)
TH
(1)
B
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
B
C2
TH
TNP: A hapten of trinitrophenyl group
TNP-C2
Anti-TNP response
The “modified” model
C2
Cytokines etc.
TNP
(2)
TH
(1)
B
Activated
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 lymphocytes
Activated & differentiated cells that may respond to
antigen binding alone to produce effector functions
• Memory lymphocytes
Cells that have experienced specific antigen previously
but need to be triggered to differentiate again to
become effector cells
Photograph copyright:
G.G. MacPherson (Oxford, 1997)
R. M. Steinman
(Rockefeller)
Dendritic cell (DC)
- The activator of naïve T cells
Dendritic cells & follicular dendritic cells are
two very different cell types
DC
FDC
Origin:
Bone marrow-derived
Haematopoietic
?
Where:
T areas,
& peripheral tissues
B follicles
Nature:
endocytic & migratory
resident
Life-span:
days
years
Present Ag:
as peptide to T cells
by MHC
as IC to B cells
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
The site of
lymphocyte activation
AL: Afferent Lymphatics
SCS: Subcapsular Sinus
PCV: Post-Capillary Venule
(HEV: High Endothelial Venule)
Organized
distribution
F
(B + FDC)
GC
+ DC
T: T cell area
B: B cell area
F: B cell follicle
GC: germinal centre
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
Ii
CLIP
Two CLASSICAL pathways
for 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)
Proteasome
(TAP-dependent)
MHC Class I
Cytosolic/
Endogenous Ag
CD4+ T
MHC Class II
Lysosome
CD8+ T
Endocytic/
Exogenous Ag
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
Cytokines etc
(2)
Naïve TH
(2)
(1)
(1)
CD28
Co-stimulations
B7
DC
B
Activated
T-B cell cooperation
CD40L:CD40
(2)
Effector TH
(1)
B
Cytokines:
IL-4
IL-5
IFNg
Abs:
IgM
IgG1, IgE
IgA
IgG2a, IgG3
(isotype switch)
Further questions:
Do DCs need to be activated?
What then activates DCs?
Vaccination: why adjuvant?
Immune system turned on
by “non-self” or by “Danger” ?