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L6 – Immune Responses: T-cells
T-cells or T-lymphocytes are distinguishable from B-cells or B-lymphocytes by
the molecules that each express on their cell surface, by the molecules that
they release and by the genes that are expressed or recombined
...
T-cells are also antigen-specific and
they have a T-cell receptor
...

However, unlike the B-cells, in order to mature, T-cells have to move to the
thymus, which is in the thoracic cavity
...
When those T-cells are developing in
the thymus, before they become mature, they have both CD4 and CD8 on
their cell-surface
...
All of these different types
of T-cells have on their cell surface the TCR, which they use to detect the
presence of the antigen to which they are specific
...
Some T-cells,
however, have an alternative version of the TCR, which is composed of a γ
and a δ chain and these T-cells are therefore, known as γδ T-cells
...

Those of the αβ T-cells also posses, amongst many other surface molecules,
CD4 or CD8 molecules
...
CD4 is a single chain polypeptide containing four Ig-like domains
packed tightly to form an extended rod that projects from the T-cell surface
...
CD8 plays a similar role to
CD4; it binds Lck, however, CD8 is a disulphide-linked heterodimer of α and β
chains, each of which contains a single Ig-like domain connected to an
extended and heavily glycosylated polypeptide projecting from the T-cell
surface
...
CD8+ T-cells are cytotoxic T-cells, which are very much like NK cells,
and CD4+, CD25+, foxp3+ T-cells are regulatory T-cells
...
MHC class I molecules are present on all nucleated cells
and present antigen peptides to CD8+ T-cells; the cells that present the
antigen-MHC class I to the TCR are known as antigen-presenting cells (all
cells excluding erythrocytes)
...

The CD4 and CD8 molecules on the surface of T-cells bind to non-

polymorphic regions of the MHC class II and MHC class I molecule
respectively
...
The TCR
has a variable and constant region similar to the antibody molecule
...
The TCR recognizes a particular peptide-MHC
combination presented on the surface of a professional antigen-presenting
cell
...
There is also an inter-chain
disulphide bond stabilizing the αβ chains
...
The antigen binding portion comprises both
the Vα and Vβ regions, within which there are hypervariable loops that give
the TCR its specificity
...
This peptide-binding groove varies enormously from one
MHC molecule to another; it is highly polymorphic
...

• When the TCR recognizes a peptide-MHC complex to which it is
specific, a signal is sent into the T-cells by molecules associated with
the TCR on the cell surface
...

For this reason, the TCR is intimately linked with the CD3 complex,
which is comprised of the invariant polypeptide chains γ and δ and two
ε chains
...
The ζ chains and the CD3 complex are
referred to as the CD3 co-receptor complex
...
These motifs are
phosphorylation sites for the kinase Lck, which is associated with CD4
or CD8
...

Activation of the T-cell requires costimulation

If the T-cell receives signals from only the TCR, it will become inactivated in a
process called anergy
...
This is a fail-safe mechanism by which T-cells do not
responds to our own molecules
...
Some of these molecules are called co-stimulatory
molecules that are able to send additional signals into the T-cells
...
This sends a signal to the
T-cell and these additional signals would activate the T-cell
...

Functional activity of T-cells
They need to expand in number so you have enough T-cells to carry out the
job required and this involves cell division and proliferation
...

The memory cells are quantitatively and qualitatively better as they can
respond stronger the next time they encounter the same pathogen
...
Cytokines are structurally diverse
polypeptides that function as messenger molecules that can communicate
from one cell to another
...

IFN-γ, which as well as being a very potent activator of macrophages, also
suppresses the activity of Th2 cells
...
In addition, they secrete TNFβ
...

Th2 cells
Through interaction with Th2 pathogen promoting products with TLRs on
dendritic cells, IL-4 is produced, which skews the development towards Th2
cells, whose cytokines (IL-4, IL-5, IL-6, IL-12 and IL-13) assist B cells and are
characteristic of humoral immunity
...
Th2 cells produce a number of
different cytokines including IL-4 and IL-13, which cause B-cells to classswitch to mainly the IgE class of antibody
...
IL-5 is important in the production of eosinophils
...
The products of Th2 cells, especially IL-4, suppress Th1 cells by
down-regulating IL-12, which together with IFN-γ is a strong determinant of
Th1 cells
...

Tc cells
They produce perforin, granzymes, FasL and cytokines and their main
function is to kill infected cells
T helper cell activation of macrophages
IFN-γ derived from Th1 cells is a very potent macrophage activator and can
also enhance the microbicidal activity of such cells to kill phagocytosed
bacteria
...
IFN-γ
stimulated macrophages leads to the production of IL-12 that leads to the
reinforcement of the Th1 phenotype
...
Dendritic cells possess
both MHC class I and MHC class II molecules and therefore, they can engage

the Th cell and the Tc precursor at the same time
...

However, the Th cell and the Tc precursor do not need to interact with the
antigen-presenting cell at the same time
...
1 and B7
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Killing by cytotoxic T-cells
Tc-cells can kill by two different mechanisms, which are identical to the killing
done by NK cells
...
The two different mechanisms are the perforin/granzymes
pathway and the Fas/FasL pathway, which are identical to the mechanisms
employed by NK cells
...

• Following activation of the Tc-cell, the cytotoxic granules move along
the cytoskeleton towards the immunological synapse, which is the point
of contact between the Tc-cell and its target
...

• The exact mechanism at work is very much debated, but it is thought
that perforin polymerises within the target cell membrane thereby
providing a channel/pore through which the granzymes can enter the
target cell
...
Granzyme A
promotes the activation of a nuclease through proteolysis of its own
inhibitor
...

• Granzyme B activates several members of the caspase family
(cysteine proteases), which can induce apoptosis by proteolysis of
several target cell proteins
...
Upon encounter of a Fas receptor-bearing cell, the Tc-cell
adheres to the cell by engagement with FasL
...

• Activated caspase-8 can damage the protein Bid, which promotes
mitochondrial permeability and release of cytochrome c into the
cytosol, but can also directly process and activate downstream

caspases such as caspase-3, which induces apoptosis in the target
cell

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