Lecture 14 - The concept of T cell activation

Question 1

What is a naive T cell?

Answer 1

this cell has the TcR on surface but has yet to encounter its antigen
has undergone positive and negative selection and is now circulating round your body

Question 2

What is a primed T cell?

Answer 2

the T cell encounters the antigen for the first time and becomes activated. It has yet to equip itself with weaponry

Question 3

What is an Activated/Effector T cell?

Answer 3

T cell is fully activated and differentiated into a cell that will deal with the pathogen

Question 4

What is anergy?

Answer 4

complete unresponsiveness of a T cell for its antigen

Question 5

How does the immune system deal with central tolerance not being absolute and B/T cells bearing receptors for host tissue?

Answer 5

The immune system deals with this adverse event by
a) restricting the recirculation of naïve B and T cells to secondary lymphoid organs and blood- ignorance of immune system
b) putting in place a two-signal pathway for activation of naive T cells
c) setting threshold limits for T cell activation
d) producing specialised regulatory T cells that suppress autoreactive activity
Collectively, the control of autoreactive cells OUTSIDE the primary lymphoid organs is called Peripheral Tolerance

Question 6

Describe how activation of T cells takes place in the secondary lymphoid organs

Answer 6

Extravasation occurs in lymph nodes and spleen but not peripheral tissues unless inflamed. Governed by restricted expression of adhesion molecules and
chemokines.
Homing of immune cells to lymph nodes is governed by CCR7 on the immune cell responding to
high levels of its ligands-CCL19 and CCL21- in the lymph node/spleen

Question 7

What happens when the TcR binds to the MHC-peptide complex on APCs?

Answer 7

Binding of MHC to TcR not sufficient for activation of T cells - requires a costimulatory signal

Question 8

What is two signal activation?

Answer 8

Important points to remember:
1) APCs and host cells can present self peptides to T cells.
2) 5-10% of recirculating T cells have receptors specific for host peptides
A T cell must receive two signals for efficient activation
SIGNAL ONE –binding of the TcR to peptide-MHC it recognises
SIGNAL TWO –binding of CD28 on T cells to costimulatory molecules CD80 or CD86 on APCs

Question 9

What happens if the naive T cell receptor only receives signal 1?

Answer 9

It becomes Anergic
If the T cell receptor comes into contact with a cell peptide in the context of MHC class I/II without costimulation not only does it not activate the T cell but it will switch the T cell off for the rest of its life - this is called anergy

Question 10

How can this two signal mechanism control activation of naive T cells?

Answer 10

Because only antigen presenting cells can express costimulatory CD80 and CD86 molecules
And, expression of these molecules on antigen presenting cells is controlled by inflammation.
Inflammation upregulates the number of peptide-MHC complexes and costimulatory molecules
above the threshold for T cell activation

Question 11

Are there any other signals required for naive T cell activation?

Answer 11

Yes, naive T cells also need a third signal that induces their differentiation into an effector cell

Question 12

How does provision of Signal One and Signal Two activate the naive T cell?

Answer 12

By initiating the construction of a complex called the immunological synapse
Reorganisation of the cytoskeleton
molecules to produce the tight junctions of the immunological synapse is called ‘capping’.
Talk between APC and T cell - APC tells type of infection, type of molecules that need to be produced, needs to stay bound.
When T cell binds to antigen in the MHC this leads to reorganisation of the cytoskeleton for all the receptors that recognise that peptide to come to that point (capping) - produces tight link, can’t pull apart

Question 13

What happens at the immunological synapse?

Answer 13

The immunological synapse brings together molecules that initiate T cell receptor signalling whilst excluding molecules that can prevent signalling via the T cell receptor
At the immunological synapse:
MHC binding to TcR
Core receptor CD4/CD8
Costimulation
Upregulation of adhesion molecules (Ig superfamily and integrins)

Question 14

What are the features of the T cell receptor?

Answer 14

The TcR has no capacity to signal
TcR is co-expressed alongside the
      CD3 complex.
CD3 complex has four subunits
e, g, d, z
CD3 complex transmits signal
     from TcR into the cell
Formation of the immunological synapse recruits kinases to CD3

Question 15

What is the role of the CD3 complex?

Answer 15

The CD3 complex contains immunoreceptor tyrosine-based activation motifs
(ITAMs).
Phosphorylation of ITAMS by kinases triggers a biochemical cascade.
Phosphorylation of CD28 amplifies the TcR signal

Question 16

How does TCR signalling work?

Answer 16

The CD3zeta (CD3z) chain
Transmits signals via TcR by recruitment of kinase Zap-70

CD4 (or CD8) acts as a coreceptor and recruits kinase
Lck

Lck triggers phosphoinositol kinase (PI3K) activity leading to cell proliferation and survival

Sum of all activations is to induce transcription of IL-2
(interleukin 2)

Question 17

How are activated T cells turned off?

Answer 17

Activated T cells must be switched off to prevent damage to host.
Such ‘switching off’ occurs following signalling through
negative costimulatory molecules.
The two most common negative costimulatory molecules for T cells are:

(a) cytotoxic lymphocyte antigen (CTLA)-4
(b) programmed death domain (PD)-1.

Question 18

Describe the negative costimulatory molecules

Answer 18

The cytoplasmic tail of CTLA-4 has an immunoreceptor tyrosine-based inhibitory motif
(ITIM).

ITIM activation recruits phosphatases to the receptor complex that de-phosphorylate
key molecules involved in T cell activation.

Like CTLA-4, PD-1 has a cytoplasmic ITIM and can dephosphorylate key molecules for
T cell activation.

Mutations of CTLA-4 or PD-1 results in an autoimmune attack on our
own tissues!