T cell activation

Question 1

what does T cell stand for?

Answer 1

Thymus selected lymphocytes

Question 2

how do T cells work?

Answer 2

remove intracellular pathogens by killing infected cells

respond to antigenic fragments presented by MHC molecules on APCs
- Fragments presented to T cells by
antigen-presenting cells
- Can’t recognise whole antigens

help B cells to become activated and produce antibodies

Question 3

types of T cells

Answer 3

1. Helper T cells (CD4+)
2. Cytotoxic T cells (CD8+)
3. Regulatory T cells (CD4+ CD25+)

Question 4

Helper T cells (CD4+)

Answer 4

Recognise ag presented on MHC class II by APCs

Th1 (IFNgamma) - activate macrophages and Tc cells

Th2 (IL-4) - activate B cells

Question 5

Cytotoxic T cells (CD8+)

Answer 5

Recognise ag presented on MHC class I on host cells

Kill virally infected cells (cancerous cells)

Question 6

Regulatory T cells (CD4+ CD25+)

Answer 6

Dampen immune response (IL-10)

Implicated in autoimmunity (T cells out of balance)

CD25+ = IL-2
=> Growth factor of T cells

Question 7

T cell receptor - structure

Answer 7

similar to antibodies

consist of alpha and beta (sometimes gamma/delta) membrane bound chains with Ig domains

associated with CD3 signalling and invariant chains CD4/8

Question 8

what do TCRs do?

Answer 8

undergo thymic selection for self-tolerance

no somatic hypermutation -> antigen affinity remains low

Question 9

2 classes of Major histocompatibility complex / Human leucocyte antigens (HLA)

Answer 9

1. MHC class I (HLA 1,2,3) - recognised by CD8+ T cells
2. MHC class II (HLA DP, DQ, DR) - recognised by CD4+ T cells

Question 10

reason why we respond to pathogens differently

Answer 10

Different MHC alleles

Presented more or less efficiently

Immune system reacts accordingly

Question 11

why are Major histocompatibility complexes / Human leucocyte antigens (HLA) important?

Answer 11

defines “self” tissue => used for organ transplant

inherit 12 genes (3 from each class from each parent) - no individual likely to be the same

Question 12

Antigen recognition

Answer 12

Requires endocytosis, processing and presentation by APC in conjunction with MHC molecule

Peptide fragments bind in groove of MHC

TCR binds across both peptide and MHC residues

CD4/8 bind MHC to prevent T cells killing APCs

Question 13

Antigen loading - MHC class I

Answer 13

[all cells]

Small peptides 8aa derived intracellularly from proteolysis

Loads into MHC in ER, required for correct MHC folding

When expressed on surface self peptides ignored, viral peptides activate cytotoxic T cells

Question 14

Antigen loading - MHC class II

Answer 14

[expressed on professional APCs]

Larger peptides 13017aa acquired by phagocytosis

Ag converted to peptides by proteolysis in endosomes + lysosomes

Pre-assembled MHC bound with invariant chain until it reaches endosome - prevents binding of self-peptides

Invariant chain replaced by peptide fragment and complex translocates to surface

Question 15

thymic selection

Answer 15

developing T cells encounter self-antigen presented on self MHC on thymic epithelial cells

Question 16

positive selection

Answer 16

if T cell DOESN’T recognise and bind to MHC -> signaled to die by apoptosis

Question 17

negative selection

Answer 17

if T cell DOES bind strongly and is activated - signaled to die by apoptosis (could be self-reacting)

Question 18

what happens to the surviving T cells after thymic selection?

Answer 18

kept alive in peripheral lymphoid organs and continual interaction with self peptide/MHC

survival signals (not growth)

Question 19

when do T cells become activated?

Answer 19

when they encounter a foreign antigen presented on self MHC

Question 20

T cell activation

Answer 20

= T cell proliferation

produces many antigen reactive clones

T cells increase in size -> blast

Increase gene transcription [IL-2 and IL-2E (CD25)]

Question 21

what happens after activation?

Answer 21

Migrate from lymph nodes to site of infection

TH2 cells bind to B cells to stimulate antigen production

Question 22

why is co-stimulation required?

Answer 22

T cells don’t activate in response to antigen alone -> TcR-peptide/MHC derived signal 1 is not enough

Normal T cell activation requires 2nd signal
Generated by co-stimulatory molecules

Question 23

what happens if the engagement of TcR (signal 1) occurs without co-stimulation (signal 2)

Answer 23

causes T cell to become unresponsive (anergic) -> leads to apoptosis

** basis of peripheral tolerance ** => autoimmunity

Question 24

example of co-stimulation

Answer 24

CD28 expressed on resting T cells, B7-2 expressed on resting APCs

Antigenic engagement of TCR leads to activation of CD28 (positive signal)

After 24-48hrs -> upregulation of CTLA-4 and B7-1 -> Inhibitory signal

Question 25

other co-stimulatory molecules that contribute to activation

Answer 25

CD-2/LFA-3

Question 26

effector responses - TH1 cells

Answer 26

Migrate to site of infection

Release IFNgamma to activate macrophages

Stimulate production of monocyte (= pre-cursors of macrophages) in BMw

Increase expression of adhesion molecules on endothelium

Induce leucocyte migration via chemokine release

=> components of acute inflammation

Question 27

effector responses - TH2 cells

Answer 27

Provides signal 2 to B cells

Question 28

Cytotoxic T cells - types of pathways

Answer 28

1. Perforin-dependent killing
   
   • Intrinsic pathway
2. Fas-dependent killing
   - Receptor mediator - extrinisic apoptotic
   pathway

Question 29

cytotoxic T cells + cancerous cells

Answer 29

Problem with targeting cancerous cells (mutated cells have self-antigens -> T cell won’t attack)

Question 30

Perforin-dependent killing pathway

Answer 30

1. Tc releases serine proteases + perforin molecules which attack target cell
2. perforin molecules assemble to form channel and serine proteases enter target cell
3. convert inactive procaspase -> active caspase via granzyme B
4. target cell undergoes apoptosis

Question 31

Fas-dependent killing pathway

Answer 31

1. Fas ligand on Tc binds to Fas on target
2. adaptor protein in target binds to Fas and triggers caspase cascade
3. inactive procaspase-8 -> active procaspase-8
4. target cell undergoes apoptosis

Question 32

what do Treg cells secrete?

Answer 32

TGBb and IL-10

Question 33

role of Treg cells?

Answer 33

anti-inflammatory

[Mutation/dysregulation of Treg activity can lead to disease]

Question 34

what do Treg pathways involve?

Answer 34

activation of Foxp3 transcription factors

Question 35

TGN1412 - The Northwick Park Trial

Answer 35

Humanised CD28 super mAb - CD28 agonist

Designed to be used in treatment of B cell chronic lymphocytic leukaemia and RA

CD28 activation in absence of TCR engagement thought to induce Treg cells and release anti-inflammatory cytokines
- Instead = cytokine storm