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Immunology (BY1IM1) > Helper T cells > Flashcards

Helper T cells Flashcards

1
Q

What do T cells look like?

A
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2
Q

Where do B cells and T cells come from?

A
  • 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
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3
Q

What distiguishes T cells from B cells?

A

The T cell receptor

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4
Q

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

A

•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).
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5
Q

TCR can be αβ or γδ

A
  • 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)
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6
Q

How many circulating T cells have αβ TCR?

A

95%

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7
Q

What do αβ T cells express?

Are they diverse?

Where are they educated?

A
  • 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
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8
Q

Do γδ T cells express CD4 or CD8?

Do they mature in the thymus?

Are they diverse?

A
  • 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
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9
Q

CD4 and CD8 bind MHC

A
  • 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
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10
Q

Explain the function of the different helper T cells: TH1

A

TH1 cells activate:

  • Macrophages
  • Killer T cells
  • B cells

Good for bacterial infection

TH1 cells secrete:

  • IFN-Gamma (IFN-γ)
  • IL-2
  • TNF-Alpha (TNFα)
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11
Q

Explain the function of the different helper T cells: TH2

A

TH2 cells activate:

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

Good for parasitic infections

TH2 cells secrete:

  • IL-4
  • IL-5
  • IL-13
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12
Q

Explain the function of the different helper T cells: TH17

A

TH17 cells recruit:

  • Macrophages

TH17 cells secretes:

IL-17

Good for chronic bacterial infections

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13
Q

Explain the function of the different helper T cells: Treg

A

Treg cells:

  • Inhibit dendritic cells
  • prevents autoimmunity
  • Supress T cell

Good for supressing immune response after infection has passed

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14
Q

Helper T cell activation (1)

A
  • 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

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15
Q

Helper T cell activation (2)

A
  • 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)
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16
Q

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

A

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

  • IFN- Gamma+ IL-12→TH1
  • IL-4 + IL-2→TH2
  • TGF beta + IL-1 + IL-6, IL-21, IL-23→ Treg
  • IL-21 + IL-17a + IL-17f + IL-22 + IL-10→ TH17
17
Q

Helper T cell activation (3)

Once activation is done:

A
  • 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
18
Q

What is the function of TH1 cytokines?

A

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 TC and NK to proliferate

19
Q

TH1 cytokines are perfect to help defend against bacterial or viral invasion

A

TH1 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

20
Q

Explain the function of TH2 cytokines

A
  • 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
21
Q

TH2 cytokines are perfect to help defend against parasitic or (rarely) bacterial infections

What happens when these responses are out of control?

A

TH2 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

22
Q

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

A

TFH cells activate B cells for:

  • Isotype switching
  • Affinity maturation
23
Q

Explain the functions of TH17 cytokines

A
  • 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
24
Q

TH17 cytokines maintain mucosal barriers and contribute to pathogen clearance at mucosal surfaces

A

TH17 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)

25
Q

What are the functions of Treg cytokines?

A
  • 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
26
Q

Treg cytokines suppress already active immune responses

A
  • Treg 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
27
Q

Why do we need all these TH cells?

A
  • Helper T cells direct the appropriate immune response by secreting the appropriate cytokines
  • The choice to be a TH1 / TH2 / TH17 / 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
28
Q

How do the T cells know what the infection is?

A
  • 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
29
Q

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

A

Molecular patterns and cytokines

30
Q

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

A
31
Q

The innate immune system directs the adaptive immune response

A
  • 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
32
Q

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

A
  1. that there is danger
  2. what the danger is
  3. where the danger is
33
Q

Helper T cells: Explain life after activation:

A
  • 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 TH have two duties:
  1. Move around the lymph nodes to provide help for TC or B cells
  2. Exit the circulation at the site of infection provide help for the cells
  • Cytokine profile expressed by effector TH is determined by co-stimulatory molecules they saw
  • Conditions at the battle ground can alter the cytokine profile expressed by helper T cells
34
Q

Explain how cytokines direct immune responses

A
  • Activated macrophages produce IL-12
  • IL-12 influences TH to secrete TH1 cytokines
  • Unbiased TH0 will become TH1, decided TH1 will be firmly committed
  • TH1 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 TH0 will be encouraged to produce TH2 cytokines (IL-4, IL-5 and IL-13) and committed TH2 are reinforced
  • TH2 cytokines are much more useful for fighting parasites
35
Q

T cells and cytokines summary (1)

A
  • 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 TH 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
36
Q

T cells and cytokines summary (2)

A
  • TH can be TH1 or TH2 – produce distinct sets of cytokines
  • Cytokines give DC clues about what and where the infection is
  • TH1 useful for bacterial and viral invasion, TH2 for parasites and mucosal infections
  • Killer T cell activation requires DC, TC and TH – sequential interaction?
  • TC 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)
37
Q

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

A

TH1→ T-bet/Stat 4

TH2→ GATA-3/ Stat5

TH17→ RORγ/Stat3

Treg→Foxp3/Stat5

Immunology (BY1IM1) (11 decks)

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