Helper T cells

Question 1

What do T cells look like?

Answer 1

Question 2

Where do B cells and T cells come from?

Answer 2

• Like B cells, T cells are ‘born’ in the bone marrow (from a lymphoid progenitor cell)
• B and T cells are descended from HSC (haematopoietic stem cells)
• BUT …B cells stay in the bone marrow whilst T cells go to the thymus (thymocytes) to mature
• T cell development is a bit more complicated than B cell

Question 3

What distiguishes T cells from B cells?

Answer 3

The T cell receptor

Question 4

The T cell receptor (TCR) distinguishes T cells from B cells

Answer 4

•The T cell receptor (TCR) resembles the B cell receptor (BCR; membrane-bound Ig)

• The T-cell receptor is a membrane-bound heterodimer composed of an α chain of 40-50 kDa and a β chain of 35-46 kDa.
• The extracellular portion of each chain consists of a C (constant) domain and a V (variable) domain.
• The three-dimensional structure formed by the four domains of the T-cell receptor resembles the antigen-binding fragment of an antibody (BCR).

Question 5

TCR can be αβ or γδ

Answer 5

• Each TCR is made up of two proteins (αβ or γδ)
• TCR protein chains are made by gene rearrangement (just like BCR)
• T cell competition is between αβ and γδ chains - whoever is successfully rearranged and expressed first is expressed on the cell surface
• γδ recognise different structures on the surface of pathogens that could incorporate carbohydrate
• αβ recognises epitopes or proteins
• T cells are either αβ or γδ (no mixtures)

Question 6

How many circulating T cells have αβ TCR?

Answer 6

95%

Question 7

What do αβ T cells express?

Are they diverse?

Where are they educated?

Answer 7

• αβ T cells express co-receptors (either CD4 or CD8)
• αβ T cells TCR are diverse (like BCR)
• αβ T cells are educated in the thymus

Question 8

Do γδ T cells express CD4 or CD8?

Do they mature in the thymus?

Are they diverse?

Answer 8

• γδ T cells don’t express CD4 or CD8
• γδ T cells seem to be important in protecting mucosal surfaces
• γδ T cells don’t mature in the thymus
• γδ T cells TCR not as diverse - limited gene rearrangement
• γδ T cells keep watch, tuned in to specific invaders

Question 9

CD4 and CD8 bind MHC

Answer 9

• Cytotoxic T cells: Any nucleated cell that can express MHC class I loads the binding groove with a peptide (end residues really important for peptide binding). This peptide is also recognised by a TCR. CD8 binds MHC class I
• Helper T cells: MHC class II expressed by antigen presenting cells load the peptide into the binding groove (middle residues really important). TCR also recognises that peptide. CD4 binds MHC class II
• CD3 is expressed by both of these cells and it is a coreceptor that transduces the antigen recognition signal

Question 10

Explain the function of the different helper T cells: T_H1

Answer 10

T_H1 cells activate:

• Macrophages
• Killer T cells
• B cells

Good for bacterial infection

T_H1 cells secrete:

• IFN-Gamma (IFN-γ)
• IL-2
• TNF-Alpha (TNFα)

Question 11

Explain the function of the different helper T cells: T_H2

Answer 11

T_H2 cells activate:

• Eosinophils
• Mast cells (IgE binds to outside of mast cells)
• Basophils

Good for parasitic infections

T_H2 cells secrete:

• IL-4
• IL-5
• IL-13

Question 12

Explain the function of the different helper T cells: T_H17

Answer 12

T_H17 cells recruit:

• Macrophages

T_H17 cells secretes:

IL-17

Good for chronic bacterial infections

Question 13

Explain the function of the different helper T cells: Treg

Answer 13

T_reg cells:

• Inhibit dendritic cells
• prevents autoimmunity
• Supress T cell

Good for supressing immune response after infection has passed

Question 14

Helper T cell activation (1)

Answer 14

• Activation of a naïve helper T cell by a dendritic cell (DC) takes hours!

1. Adhesion molecules on DC bind their partners on T cell – brings cells into close contact→Non-specific, weak binding
2. Lets the T cell peek at the MHC II: peptide displayed
3. If the T cell doesn’t recognise the peptide, cells break apart
4. If the T cell sees its cognate antigen:

CD4 clips onto MHC II – strengthens binding

More adhesion molecules are expressed and engage – strengthens binding

Question 15

Helper T cell activation (2)

Answer 15

• Engagement of helper T cell receptors upregulates CD40L expression
• CD40L binds CD40 on DC
• This signals to DC:
• DC increases expression of MHC II and co-stimulatory molecules (e.g. B7)
• DC secretes cytokines that prolong its life
• Keeps useful DC alive long enough to interact with naïve T cells and maintain the immune response
• Interaction is a two-way street
• End result:
• more potent DC
• more useful helper T
• (expressing CD40L to allow it to activate B cells)

Question 16

There are more than one type of helper T cell, what cytokines mediate differentiation to specific helper T cells?

Answer 16

From naiive CD4 T cell these cytokines mediate differentiation to specific helper T cells:

• IFN- Gamma+ IL-12→T_H1
• IL-4 + IL-2→T_H2
• TGF beta + IL-1 + IL-6, IL-21, IL-23→ T_reg
• IL-21 + IL-17a + IL-17f + IL-22 + IL-10→ T_H17

Question 17

Helper T cell activation (3)

Once activation is done:

Answer 17

• T cell and DC break apart
• DC carries on to activate more T cells
• Activated T cell proliferates in response to IL-2
• Only activated T cells express IL-2R (receptor)
• Newly activated T cells double in number every 6h
• Clonal selection in the T cell world

Question 18

What is the function of T_H1 cytokines?

Answer 18

IFN-γ​ primes macrophages, influences B cells to class switch to IgG3 (good for opsonising and activating complement)

TNF-α activates primed macrophages and NK cells

IL-2 stimulates T_C and NK to proliferate

Question 19

T_H1 cytokines are perfect to help defend against bacterial or viral invasion

Answer 19

T_H1 cytokines help instruct the innate and adaptive immune systems to produce the right defences (cells and opsonising antibodies) that will be effective against these dangers

Question 20

Explain the function of T_H2 cytokines

Answer 20

• IL-4 is a growth factor for B cells, vital for class switching to IgE
• IL-5 promotes IgA production and prolongs eosinophil survival
• IL-13 induces matrix metalloprotease (MMP) expression

Question 21

T_H2 cytokines are perfect to help defend against parasitic or (rarely) bacterial infections

What happens when these responses are out of control?

Answer 21

T_H2 cytokines help instruct the innate and adaptive immune systems to produce the right defences (antibodies and activated eosinophils) that will be effective against these dangers

when these responses are out of control they are associated with allergy

Question 22

Explain the function of the different helper T cells: T_FH (follicular helper cells)

Answer 22

T_FH cells activate B cells for:

• Isotype switching
• Affinity maturation

Question 23

Explain the functions of T_H17 cytokines

Answer 23

• IL-17 activates many signaling pathways, including NF-κB, resulting in the expression of other cytokines, chemokines, matrix metalloproteinases, and antimicrobial peptides; also enhances neutrophil recruitment
• IL-21 activates NK cells and TC (antiviral responses)
• IL-22 stimulates inflammatory responses, S100s and defensins; can be either pro-inflammatory or protective depending on the local IL-17 level

Question 24

T_H17 cytokines maintain mucosal barriers and contribute to pathogen clearance at mucosal surfaces

Answer 24

T_H17 cytokines help instruct the innate and adaptive immune systems to produce the right defences (cells and soluble mediators), but if left unchecked can cause tissue damage (autoimmunity) and fibrosis (scar formation)

Question 25

What are the functions of T_reg cytokines?

Answer 25

* **TGF-β** inhibits the activity of many inflammatory cell types * **IL-35** suppresses T cell activity and inhibits angiogenesis (the formation of new blood vessels) * **IL-10** downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages

Question 26

T_reg cytokines suppress already active immune responses

Answer 26

* T_reg cytokines control the immune response once the danger has passed (resolution stage); however, sustained * Treg activity can lead to fibrosis (scar formation) via chronic TGF-β signalling

Question 27

Why do we need all these T_H cells?

Answer 27

* Helper T cells direct the appropriate immune response by secreting the appropriate cytokines * The choice to be a T_H1 / T_H2 / T_H17 / Treg cell occurs at the site of inflammation after they leave the lymph node- very plastic (flexible cells) so can change their idenity when required * This local environment cytokine signalling gives the immune system flexibility to respond to different invaders in different parts of the body

Question 28

How do the T cells know what the infection is?

Answer 28

* Dendritic cells (DC) are the ‘brains’ of the outfit * DC collect information on the nature of the invasion and decide how the immune system should react * DC = APC→activate T cells * DC collect data on the infection and take it to the T cells in the lymph nodes

Question 29

There are two types of intelligence gathered at the battle site:

Answer 29

Molecular patterns and cytokines

Question 30

Draw a diagram to show the different cells that interact with the different T cells

Answer 30

Question 31

The innate immune system directs the adaptive immune response

Answer 31

* DC sit under exposed surfaces (skin, respiratory epithelium), waiting for information on any breach of the physical defences * DC receptors collect information (patterns and cytokines) * DC travel to the nearest lymph node and express specific sets of co-stimulatory molecules to pass the info on to helper T cells * Helper T cells now know what weapons they need to mobilise and where to take the weapons to

Question 32

What does the innate immune system (DC) inform the adaptive immune system (T_H) about?

Answer 32

1. that there is danger 2. what the danger is 3. where the danger is

Question 33

Helper T cells: Explain life after activation:

Answer 33

* Activated T cells proliferate rapidly (few days) * Re-stimulation will drive more proliferative cycles * Then they get bored with this and get a proper job…they mature into “effector cells” * Effector T_H have two duties: 1. Move around the lymph nodes to provide help for T_C or B cells 2. Exit the circulation at the site of infection provide help for the cells * Cytokine profile expressed by effector T_H is determined by co-stimulatory molecules they saw * Conditions at the battle ground can alter the cytokine profile expressed by helper T cells

Question 34

Explain how cytokines direct immune responses

Answer 34

* Activated macrophages produce IL-12 * IL-12 influences T_H to secrete T_H1 cytokines * Unbiased T_H0 will become T_H1, decided T_H1 will be firmly committed * *T_H1 cytokines (IFNg, TNF and IL-2) produce the ideal defence against bacteria or viruses**​* * In parasitic invasions, the environment is full of IL-4 * Now uncommitted T_H0 will be encouraged to produce T_H2 cytokines (IL-4, IL-5 and IL-13) and committed T_H2 are reinforced * *T_H2 cytokines are much more useful for fighting parasites*

Question 35

T cells and cytokines summary (1)

Answer 35

* TCR has ligand binding (αβ) and signalling (CD3) domains * TCR needs co-receptors for signalling (CD8 or CD4) * CD8 and CD4 differentiate killers (look for intracellular infections) from helpers (help with extracellular infections) * TCR on T_H finds cognate antigen in MHCII of APC, * CD4 binds MHCII * strong interaction upregulates CD40L which binds CD40 on APC and upregulates APC expression of MHCII and B7 – co-stimulation amplifies T cell response * DC and Helper T cell interact to activate each other

Question 36

T cells and cytokines summary (2)

Answer 36

* T_H can be T_H1 or T_H2 – produce distinct sets of cytokines * Cytokines give DC clues about what and where the infection is * T_H1 useful for bacterial and viral invasion, T_H2 for parasites and mucosal infections * Killer T cell activation requires DC, T_C and T_H – sequential interaction? * T_C enter into hand-to-hand combat, deliver perforin and granzymes to target cells * TC induce apoptosis in targets (tidy death) * Most activated T cells will die by ACID, some become memory cells ready for subsequent infections (secondary responses)

Question 37

What transcription factors do each of the T cells turn on?

Answer 37

T_H1→ T-bet/Stat 4 T_H2→ GATA-3/ Stat5 T_H17→ RORγ/Stat3 Treg→Foxp3/Stat5