1. Development of CD8+ T cells in the thymus
Double negative T cell
Lymphoid
progenitor
Double positive T cell
Cortical epithelial
cell
Death by
Neglect due to
Weak signalling
CORTEX
MEDULLA
CD8 committed T cell
CD4 committed T cell
THYMUS
Medullary epithelial cell Or
Dendritic cell
CD8 T cell
Negative selection
and death
Positive
selection
TO THE
PERIPHERY!
Hematopoietic precursor cells arrive to the thymus and become lymphoid progenitor cells in the cortex. These cells are CD3-/CD4-/CD8-, double negative cells, but soon start to express CD3 and T cell receptor (TCR). Next these cells begin to express both CD4 and CD8 molecules and become double positive T cells. At this stage double positive T cells interact with cortical epithelial cells. Some cells undergo apoptosis due to weak TCR-signalling. Depending if the double positive T cells recognize MHC I or MHC II via their TCR, they become committed double positive T cells. The committed T cells migrate to the medulla of thymus and stop expressing CD4 or CD8, depending on the initial recognition of MHC I or MHC II. CD8 cells recognize MHC I and stop expressing CD4. After they have become single positive CD8 cells they interact with medullary epithelial cells and either undergo apoptosis (negative selection) due to self-reactivity, or develop to mature CD8 T cells which exit from the thymus to the periphery as naïve CD8+ T cells.
Raine Toivonen

2. Activation of CD8+ T cells in the peripheryAg
TCR
CD28
IL-2
IL2R
CD8
Dendritic cell
MHC I
CD80 / CD86
CD8+ T cell encounters an activated APC
The APC presents antigen on its surface within MHC I
Antigens can be bound to MHC I either when they are synthesized within the cell (endogenous or viral antigens) or transferred from phagosomes to cytosolic compartment (cross-presentation of exogenous antigens)
CD8 T cell produces IL-2 to drive its own proliferation
CD8 T cells can be activated when they encounter an activated professional antigen presenting cell (dendritic cell, DC) within organized lymphoid tissue (such as a lymph node).
In order to become activated by a DC, the DC must present an antigen to the CD8 T cell within MHC I. Antigens are presented within MHC I when they are synthetized by the cell (self antigen, viral or tumor antigen), or phagocytosed by the cell and transferred from phagosomes to the cytosolic compartment (exogenous antigens, especially membrane bound or particulate).
The CD8 T cell recognizes the antigen and MHC I with its specific T-cell receptor. CD8 molecule interacts with the MHC I molecule of the APC to stabilize T-cell receptor ligation (”trimolecular complex”). CD80 and/or CD86 interact with CD28 to provide costimulation during activation. The interaction between CD28 and CD80 / CD86 helps the CD8 T cell e.g. to produce IL-2 and to drive its own proliferation.
Raine Toivonen

3. The DC is activated by CD4+ T cell: license to killAg
TCR
CD8
IL12R
DENDRITIC CELL
MHC I
CD4
CD28 B7
(CD80 / CD86)
CD4+ T HELPER CELL
CD40L
CD40
In many cases, activation of CD8+ T cells to become cytotoxic effector cells (cytotoxic T lymphocytes, CTL) requires CD4+ T-cell help.
The CD4+ T cell recognizes its specific antigen within MHC II on the same dendritic cell. While becoming activated itself, the CD4+ T cell augments activation of the DC e.g. by CD40-CD40L signalling.
CD40 pathway enhances the expression of both MHC I and B7 costimulatory ligands, as well as induces the production of cytokines.
Raine Toivonen

4. Killing mechanisms Perforin/Granzymes DNA CASPASE Raine Toivonen CTLAg
CTL
Infected cell
CASPASE
DNA
Activated CD8+ T cells differentiate to effector cells called Cytotoxic T Lymphocytes (CTL). CTL contain perforins and granzymes within their cytotoxic granules. After recognition of the target cell expressing its cognate antigen whithin MHC I, the CTL makes a contact with its target cell and releases its cytotoxic granules to the membrane of the target cell. Perforins attach to the plasma membrane of the target cell and enable the granzymes to enter the target cell. Granzymes are serine proteases, which cleave procaspases to biologically active caspases. Active caspases lead to cell death by apoptosis, which involves multiple mechanisms including cleavage of DNA by activated DNAses.
Raine Toivonen

5. Killing mechanisms 2. FAS / FAS ligand DAXX RIP1 FADD RAIDD DISC
CTL
Infected cell
DISC
DAXX
RIP1
FADD
RAIDD
CASPASE 2
ASK1
ProCASPASE 8
CASPASE 8
Another mechanism of target-cell apoptosis which can be executed by an activated CTL is activation of receptor-mediated apoptosis. Activated T-cells including CTL express FAS Ligand (CD95L) which binds and multimerizes Fas receptors on the target cell. The intracellular part of each Fas receptor contains a domain (death domain) which interacts with intracellular apoptosis machinery, including FADD and Caspase 8/10. Clustering of FADD and Caspase 8/10 creates death-inducing signaling complexes (DISC), which lead to activation of downstream executive caspases and subsequent apoptosis of the target cell. Ag
CASPASE 3
JNK
APOPTOSIS
Raine Toivonen