Recipient CD8 T Cell

1
Alloantigen Recognition by T Cells
Direct Presentation
Recipient CD4 T Cell
Recipient CD8 T Cell
TcR
TcR
Peptide
MHC class II
MHC class I
Donor APC
Indirect Presentation
Recipient CD4 T Cell
Recipient CD8 T Cell
Exogenous (Donor) Antigen
TcR
TcR
Peptide
Peptide
MHC class II
MHC class I
Recipient APC
2
Alloantigen Presentation Sites
Lymphatics
Lymph Node
Dendritic Cells
Graft
Free Alloantigens
Alloantibodies
Peripheral Blood
Mo and T Cells
Spleen
Graft APC
self Mo
donor Mo
donor Endo
donor Tissue cells
3
The T Cell Alloactivation Process
Other Signals (Cytokines)
Immunologic Synapse
Intracellular Signals
Integration Level 2
Integration Level 1
Antigen Costimulation
DNA Binding Proteins
Lipid Raft
Integration Level 3
T Cell Behavior
TH1/TH2
TCR
TH3/TR1
Gene Expression
Costim. Receptors
Anergy
Apoptosis
4
Costimulation Can Activate or Deactivate T Cells
Naïve T cell
Activated T cell
Deactivated T cell
MHC
MHC
TcR
TcR
TcR
Ag
Costim
APC
APC
Ag
Costim
Activating Costimulation Receptor
Deactivating Costimulation Receptor
Costimulation Ligand
Costimulation Ligand
CD40L
CD40
CD28
CTLA-4
B7.1/B7.2
B7.1/B7.2
ICOS
PD-1
ICOS-L
PD-L1/PD-L2
LFA-1
ICAM-1
5
Cytokine Environment Directs T Cell Behavior
Pro-Inflammatory Response
Prototpic Pro-Inflammatory Cytokine
IFNg
IFNg
Antigen
IFNg
APC
Costimulation
Naïve T cell
TH1
Antigen Presenting Cell
Pro-Inflammation
APC activation
TH1 activation
Endothelial activation
6
Some Effects of IFNg A Prototypic
Pro-Inflammatory Cytokine,
Increases
Systemic expression of MHC class II
JI 148 3837, 1992
Expression of pro-inflammatory chemokines
IP-10
J Exp Med 166 1084, 1987
MIG
J Exp Med 173 417 1991
Endothelial Activation
ICAM-1
JI 137245, 1986
VCAM-1
JI 146 592, 1991
TH1 activation
JI 14350 4494, 1993
Decreases
TH2 activation
JI 140 4245, 1988
7
Control of Pro-Inflammatory T Cell Behavior
Mechanism
Effect on T Cells
Lack of costimulation
Anergy
Negative Costimulation (CTLA-4, PD-1)
Failed Activation
Lack of growth factors (IL2)
Apoptosis
Immune Regulation (TGFb, IL10, others)
Functional Diversion
Apoptosis
Cell Deletion (Fas/FasL)
8
Cytokine Environment Directs T Cell Behavior
Anti-Inflammatory Response
Prototypic Anti-inflamatory Cytokine
TGFb
TGFb
Antigen
TGFb, IL10
APC
Costimulation
Naïve T cell
TR
Antigen Presenting Cell
Anti-Inflammation
APC de-activation
TH1/TH2 de-activation
Endothelial de-activation
9
Some Effects of TGFb A prototypic
Anti-Inflammatory Cytokine,
Decreases
Cytokine production/proliferation by resting T
cells
JI 167 773, 2001
Activation of TH1 cells
IL12, CD40 expression by Mo
JI 1601589, 1998
Activation of TH2 cells
JI 165 4473, 2000
IFNg-induced MHC expression by Mo
JI 158 2065, 1997
Endothelial e-selectin and lymphocyte homing
JI 150 4494, 1993
Increases
IL10 production by Mo
JI 160 2089, 1998
Activation of regulatory T cells
JI 166 7282, 2001
10
Immune Responses Reflect Shifts in the Balance
Between Pro-Inflammatory and Anti-Inflammatory
Processes
Pro-Inflammation
Anti-Inflammation
Impairs Destructive Responses
Favors Destructive Responses
Chronic Infection
Clearance of Infectious Agents
Acceptance of Allografts
Rejection of Allografts
Destruction of Tumors
Survival of tumors
Autoimmunity
Control of Autoimmunity