L13: CTL and Th cells as effectors

Question 1

General characteristics of effector T cells (5)

Answer 1

1. Changes in adhesion molecules: Naive T cells have L-selectin (rolling adhesion) - home to lymph nodes. Effector cells have downregulated L-selectin, integrin molecules VLA-4 - bind to endothelium at inflammatory sites.
2. Cease reciruclation. Travel from lymph node via blood to infected sites - altered chemokine receptors
3. Respond to displayed MHC-peptide without costimulation (only needs 1 signal)
4. Bind to target cell, polarisation of receptors and effector molecule secretion
5. CTL or T helper functions (Th1 and Th2)

Question 2

CD8 T cell main function

Answer 2

Cytotoxic T cells kill via apoptosis and can destroy multiple cells. CTL recognises and binds virus-infected cell, inducing apoptosis. The same CTL can migrate to a new target cell and based on signalling, it can kill the cell or move onto the next cell. CTL regenerate their lytic granules for multiple targets

Question 3

Main components of lytic granules (4)

Answer 3

Perforin: aids in delivering contents of granules into the cytoplasm of target cell
Granzymes: serine proteases, which activate apoptosis once in the cytoplasm of the target cell
Granulysin: has antimicrobial actions and can induce apoptosis
Seyglycin: acts as a scaffold, preventing the granules from having an active effect in the CTL

Question 4

Additional CD8 T cell functions (2)

Answer 4

1. FasL expression - lead to target cell death, most important in lymphocyte homeostasis and removing Fas bearing, activated T cells after resolution of infection
2. Secretion of cytokines: (a) IFN-g promotes macrophage activation, increases antigen processing and directs anti-viral effects; (b) TNFa (tumour necrosis factor) and LTa (lymphotoxin) aid in macrophage activation and can induce cell apoptosis through TNF receptor 1 signalling

Question 5

Homing of effector T cells to inflammatory sites

Answer 5

Naive T cells use L-selectin on HEVs of LNs. Effector T cells use VLA-4 which binds to VCAM-4. Skin-homing lymphocytes bind E-selectin and the chemokine CCL17 on vascular endothelium. CCL27 binds CCR10 on skin-homing effector cell.

Question 6

Granzyme induction of cell death (5)

Answer 6

1. Engagement of TCR by peptide:MHC complex causes directed release of perforin and granzymes complexed with serglycin
2. Granzyme is delivered into cytosol of infected cell and targets BID (BH3-interacting domain death agonist protein) and pro-caspase-3
3. Granzyme delivered into the cytosol of infected cell and targets BID and pro-caspase-3
4. Truncated BID (tBID) disrupts mitochondrial outer membrane, and activated caspase-3 cleaves ICAD (inhibitory CAD protein), releasing caspase-activated DNase (CAD)
5. Release of cytochrome c into cytosol activates apoptosis and CAD induces DNA fragmentation.

Question 7

CD4 T cells: peptide + MHC class 2 (5)

Answer 7

1. Th1: IFN-y - gets rid of bacteria and assists with phagocytosis
2. Th2: IL4, 5, 13 - make antibodies and expel large parasites
3. Th17: IL17 - pro-inflammatory and ensures that neutrophils are recruited to site of infection
4. TFH: IgM - sit around B cell follicles and aid in antibody production. Helps with isotype switching and affinity maturation
5. Treg: suppress immune responses important post-infection

Question 8

Th cell subset cross-regulation

Answer 8

Th2 produces IL-4, 10 to inhibit Th1. IL-10 feeds onto APC to inhibit IL-12 which is the inducing signal for Th1 cells. Th17 can be inhibited by both Th1 and Th2.

Question 9

Functions of Th1 CD4+ T cells (6)

Answer 9

1. IFN-y and CD40 ligand: activates macrophage to destroy engulfed bacteria
2. Fas ligand or LT-b: kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages
3. IL-2: induces T-cell proliferation increasing numbers of effector cells
4. IL-3 + GM-CSF: induces macrophage differentiation in the bone marrow
5. TNF-a and LT-a: activates endothelium to induce macrophage binding and exit from blood vessel at site of infection
6. CXCL2: causes macrophages to accumulate at site of infection

Question 10

CD4 T cell priming of the CD8 T cell response

Answer 10

CD4 interacts with APC and primes it so it enhances CD8 response. Interaction between CD40L and CD40 causes positive signals in the APC to upregulate costuimulatory molecules. CD4 moves off the APC for a CD8 cell to encounter the APC with enhanced costimulatory molecules.

Question 11

Treg development

Answer 11

In absence of infection, DCs make TGF-b and little IL-6. CD4 T cells activated to express Foxp3

Question 12

Th17 development

Answer 12

Infection with certain pathogens induces DCs to express high levels of IL-6. Naive CD4 T cells respond by expressing RORyT and become Th17 cells

Question 13

Regulator T cells (Treg) (3)

Answer 13

1. Treg cells suppress proliferation of other T cells and induce tolerance, suppress autoimmune cells escaping the thymus
2. Several routes for generation: natural develops in the thymus, induced developed in the periphery by interaction with tolerogenic DC
3. Treg works via suppressing APC or T cells, or through release of immunosuppressive cytokines like IL-10 and TGF-b

Question 14

Natural Treg (4)

Answer 14

1. Suppress autoreactive T cells - CD25 is a marker of natural Treg cells
2. If not present there is a lot of autoimmunity
3. Moderate affinity recognition of self peptide by CD4+ CD25+ cells in the thymus leads to survival
4. Foxp3 deficiencies lead to deficiency in Tregs - multi organ autoimmunity

Question 15

Th17 function (5)

Answer 15

1. Inflammatory bowel disease
2. MS
3. Psoriasis of skin
4. Rheymatod arthritis
5. Infection