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SEM 4: Immunology > Generation of Diversity in The T Cell Repertoire > Flashcards

Generation of Diversity in The T Cell Repertoire Flashcards

1
Q

Define an antigen

A

Any molecule that can bind specifically to an antibody e.g. grass pollens or HIV gp120.

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2
Q

What is an antigen in terms of everyday science?

A

Usually refers to proteins, carbohydrates and lipids capable of binding to B-cell receptors, T-cell receptors and/or innate immune receptors. They are usually immunogenic so produce an immune response in the host.

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3
Q

What is an epitope?

A

A small portion of an antigen. That is used as a target for antibodies also for MHC and TCRs. One antigen can have multiple epitopes.

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4
Q

Where do adaptive immune responses occur on antigen?

A

Occur on specific epitopes.

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5
Q

What is the connection between vaccination, infection and epitopes?

A

Infection and vaccination usually induce polyclonal T-and B-cell responses so multiple epitopes can be recognised on a single antigen.

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6
Q

What is the key difference between B cells and T cells?

A

B cells will recognise an unprocessed intact antigen (protein or whole microbe) which will be enough for the cell whereas a T cell will not be able to recognise an unprocessed antigen.

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7
Q

What happens when the B cell recognises the unprocessed antigen?

A

It will proliferate and make multiple clones of the original B cell - clonal expansion.

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8
Q

How is the antigen recognised by T cells?

A

The antigen is processed and multiple peptides are made by proteolytic enzymes which are then presented on the surface of an antigen presenting cell (APC). This will form a complex with the MHC molecules and activate the T cell one it sees the APC on the surface.

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9
Q

What type of APC is needed to produce a T-cell response?

A

Need a live and viable APC that is not fixed as these produce additional signals that only viable cells can produce to activate signals.

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10
Q

How are exogenous antigens uptaken by APCs?

A

Through:

  • Phagocytosis
  • Controlled membrane uptake: membrane Ig receptor mediated uptake
  • Pinocytosis
  • Complement receptor mediated phagocytosis
  • Fc receptor mediated phagocytosis
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11
Q

Which immune cells recognise and process antigens?

A
  • B-cells (rarely and less efficiently than dendritic cells)
  • Mialy cells: monocytes (found in blood) and macrophages (terminally differentiated in tissue)
  • Dendritic cells which are derived from monocytes - most advanced APC
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12
Q

Where are macrophages and dendritic cells found?

A
  • Both rare in peripheral blood but enriched in mucosal tissues that have direct contact with the external environment.
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13
Q

Function of macrophages and dendritic cells

A

Highly phagocytic cells that induce strong T-cell responses and inflammation. They are important for protection against Mycobacterium tuberculosis

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14
Q

Why are macrophages better equipped to kill pathogens that dendritic cells? What are dendritic cells better at?

A

They have a higher NO production whereas DCs are better at migrating to lymph nodes via CCR7 and presenting antigen to T-cells. They are both specialised but ultimately have overlapping functions.

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15
Q

Why is the structure of dendritic cells important?

A

Have multiple dendrites to increase the cell surface and interaction with the environment. They are extensions of the cell membrane.

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16
Q

Describe the structure of B cells and why it is important

A
  • has a membrane antibody on its surface that can capture an antigen and present it to other B-cells and t-cells.
  • Found highly abundant in blood and mucosal tissues
  • Receptor-mediated internalisation of antigens, as opposed to phagocytosis.
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17
Q

What is the primary function of B-cells?

A

To make antibody (plasma cells) - still good for antigen presentation but not the main role. Possibly main inducer of the T-cell immune response to pathogens such as Neisseria meningitidis

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18
Q

What are the two types of antigen processing?

A

Endogenous and Exogenous

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19
Q

Describe the simple process of antigen processing

A
  1. Uptake of antigen from an APC
  2. Degradation into smaller peptides by synthesis in the cytoplasm through proteolytic degradation
  3. Antigen-MHC complex formation by loading the peptide antigens on MHC class I molecules or MHC class II which is different
  4. Transport and expression of antigen-MHC complexes on the surfaces of cells for recognition by T cells.
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20
Q

Why is endogenous presenting needed?

A

It is needed because some cell types do not have a lysosomal system like macrophages but still need to present to other cells. Lysosomal systems are specialised for motility, phagocytosis and introduction of particles.

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21
Q

What is endogenous presenting?

A

It is a non-lysosomal mechanism to process antigens for presentation to T-cells done by the cytosol. It is the path used for example with cells infected with viral proteins.

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22
Q

How are peptide antigens produced in the cytosol physically separated by MHC class I and how do they overcome this?

A

The peptides are cleaved in the cytosol by the proteosome and are physically separated by the ER so need to access the ER to be loaded onto MHC class I molecules.

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23
Q

Which viral antigens are processed via endogenous and exogenous pathways, respectively?

A

Antigens from inactive viruses = endogenous

Antigens from infectious viruses= exogenous.

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24
Q

Summarise the endogenous pathway

A
  1. Antigen is processed into the cytosol.
  2. Cleaved into multiple peptides by proteosome
  3. Enters the ER and is presented on the MHC class I molecules on the surface.
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25
Q

Summarise the exogenous pathway

A
  1. Antigens are phagocytosised by macrophages and dendritic cells
  2. Sequestered to lysosomes or endosomes
  3. Processed and loaded onto MHC class II molecules in the lysosomes
  4. Presented on the surface of the cell
26
Q

What is the difference between the two types of presentation?

A

They activate different types of T cells. For example, MHC II will activate a CD4 T cell which has distinct functions from a CD8 cell. They differ in function and phenotype - expressing either CD4 or CD8 antigens on their surface.

27
Q

How does the function of the different T cells direct to the different presenting pathways?

A

Pathogens that reside in phagolysosomes such as M. tuberculosis are directed to the endogenous processing and killed by cytotoxic T cells or macrophages themselves.

28
Q

Characteristics of MHC Class I

A
  • Expressed on all nucleated cells -> not in RBC as it does not have a nucleus
  • Binds short peptides (8-10 amino acids)
  • Presents to CD8+ T-cells
  • Antigens from the cytosol (+cross-presentation)
29
Q

Characteristics of MHC Class II

A
  • Expressed on APCs and activated T-cells
  • Long peptides (typically 15-24 amino acids)
  • Presents to CD4+ T-cells
  • Antigens from phagosomes and endosomes
30
Q

What is a common feature of MHC Class I and II?

A

They have a peptide groove where the peptide binds and interacts with domains. Any modification of the structure, then it cannot bind peptides.

31
Q

Where is MHC Class I found mostly?

A

Class I is present everywhere but not at the same density - epithelial cells have a low density
- Found a lot in the rest of the lymphoid tissues: T-cells, B-cells, macrophages, other APC and neutrophils

32
Q

Where is MHC Class II found mostly?

A

Found in B cells, other APC and epithelial cells of the thymus

33
Q

Why is histocompatibility important and which is the most common?

A

Class I:

  • HLA-A
  • HLA-B
  • HLA-C

Class II:

  • HLA-DM
  • HLA-DO
  • HLA-DP
  • HLA-DQ
  • HLA-DR

It is important to check the histocompatibility for example in organ transplants otherwise the organ will be rejected. This determines the compatibility of the genotypes and blood type for organ transplant.

34
Q

What does the T-cell Receptor do?

A

It binds to peptide-MHC (pMHC) complexes and cannot recognise peptides alone. The receptor needs to find the peptide groove in the APC and recognise the peptide complex with the MHC molecule. It exists in a TCR complex with accessory molecules such as CD3.

35
Q

Similarities between T and B cell receptors

A
  • Both belong to Ig superfamily
  • Like Fab fragment of antibody: this is the antibody binding site on the tip of the molecule
  • Large diversity
  • Once produced, has a single specificity
36
Q

Differences between T and B cell receptors

A
  • TCR has a low affinity for antibodies in terms of Kd than BCR
  • TCR cannot be released whereas antibodies can become circulating when released from the B cell surface
  • No Fc fragment, so no cellular functions
  • Single rather than two binding sites like in antibodies
  • BCR/Ab have 5 classes whereas TCR has only 2 classes (aB and yD)
37
Q

How does T cell receptor recombine for different combinations?

A

Germline DNA -> recombination -> rearranged DNA -> transcription splicing translation -> forms protein (T-cell receptor) for both the alpha and beta classes or gamma and delta classes.

38
Q

How does TCR diversity occur?

A

Similar to B cell receptor diversity. This is achieved through before antigen stimulation: somatic recombination and after antigen stimulation: somatic hypermutation. Whereas, T cells diversity is generated before antigen stimulation through somatic recombination but lacks the somatic hypermutation which explains the lower affinity.

39
Q

When the APC presents the peptide, it is activated by the T cell. What is the three signal model that activates the T cell?

A

Signal One: Direct interaction between the antigen and the T-cell

Signal Two: Co-stimulatory signal from the APC by accessory receptors

Signal Three: Cytokine secretion

These go on to induce other pathways usually kinases that are activated following ligation of the T-cell receptor and co-stimulatory molecules. This activates transcription factors and gene expression.

40
Q

How does signal one further activate the T-cell?

A

When there is direct interaction between antigen and the T-cell. This is through the T-cell receptor and the peptide-MHC. This activates the naive T-cell.

41
Q

How does signal two further activate the T-cell?

A

Through co-stimulation, a signal is delivered from APC by germline-encoded accessory receptors which are part of the B7 family (CD80 and CD86). These bind to their corresponding partners on CD8 T cells and CD4 T cells.

42
Q

How does signal three further activate the T-cell?

A

This is required for a strong response and determing T-cell phenotype. It amplifies the response by secreting cytokines by the APC to determine the T-cell phenotype.

43
Q

Which cytokines are released by the APC to amplify the T-cell response?

A

IL-12: promotes Th1 cells
IL-4: promotes Th2 cells
IL-23: promotes Th17 that is a subclass of helper T cells.

44
Q

Describe the immunological synapse

A
  • There are multiple interactions between the pMHC and the T cell receptor, however this interaction has a lower affinity so it is short lived.
  • Additional interactions occur for example, the stimulatory molecule: CD80/86 or B71/B72 interacting with their partners CD28/CTL4.
  • This strengthens the interaction between the two cells and stimulates the activation of the T cells.
  • Integrins and others also keep the cell in contact for longer.
45
Q

Difference between CD4 and CD8 cells

A
  • CD4+ are helper T cells.
  • CD4+ Th1 and Th2 will produce cytokines that will activate other cells such as macrophages (Th1) that will kill intracellular pathogens with teh cytokines. The Th2 will produce cytokines that activate B-cells that produce antibodies that neutralise viruses or prevent colonisation of infectious bacteria.
  • Cells that express predominantly CD8+ are called cytotoxic T cells. It will directly kill infected cells whereas CD4+ is more indirect. For example, a CD8+ will recognise a viral infected cell expressing an MHC class I peptide on the surface. It will contact the cell and kill it.
46
Q

Why is an overly-vigourous immune response harmful?

A

It is harmful to the host as it will damage more tissue that is not needed.

47
Q

Why are negative regulators important?

A

The T-cells can be curbed so they are not excessively activated and causre more damage to the tissue. Negative regulators of antigen presentation provide an ‘immune checkpoint’ to limit T-cell activation to achieve homeostasis. What is retained is the memory T cell and be reactivate if attacked from the same virus again.

48
Q

What are the two important molecules that are negative regulators of antigen presentation?

A
  • CTLA4 (cytotoxic T-lymphocyte-associated protein 4)
  • PD-L1 (programmed Death-ligand 1)

That are cruical for dampening the T-cell response. These are regulatory molecules on T cells which are responsible for regulating the immune response.

49
Q

Describe the mechanism of PD-L1 and CTLA-4 inhibition of T-cell function

A
  1. The T-cell receptor interacts with APCs and is activated
  2. PD-L1 receptor is expressed on T-cells so when activated by PD-L1 it leads to blockade of the receptor. This is through multiple signalling pathways but the end product is the stop of the T-cell activation. SHP-2 dephosphorylates TCR signalling molecules.
  3. Similarly, CTLA-4 molecule acts on the co-stimulatory molecule (CD28) and competes with CD28 for APC ‘attention’.

This is used in cancer therapy.

50
Q

How do T-cells stop self antigens from being recognised?

A

This is done through negative selection or apoptosis as T-cells should not recognise self-antigens from our own bodies. T-cells clones are deleted from the cell repertoire.

51
Q

Describe the process of negative and positive selection

A
  1. T-cell arises from thymus and is exposed to self-antigens to test for reactivity.
  2. T-cells that can’t bind self antigen-MHC are deleted -> positive selection as they won’t be able to protect against pathogens.
  3. T-cells that can bind self antigen-MHC too strongly are also deleted -> negative selection as they are too dangerous as too self-reactive.
52
Q

What is the stochastic model?

A

This is a complex regulatory mechanism that involves Treg (thymically-derived) which is involved in the selection of self-reacting T cells.

53
Q

What controls the Treg cells?

A

Characterised by expression of FOXP3+ which is the master gene controller for Treg. These T cells regulate self-reacting T-cells by induce self-apoptosis or deletion through the release of interleukin 10 and TGF-beta.

54
Q

What are organisms that depend on the human host for survival called?

A

Obligate parasites.

55
Q

How does mycobacterium tuberculosis affect the human host?

A
  • Upregulates PD-L1 on APCs to shut down T-cell activation

- Blocks MHC Class II expression via multipel mechanisms

56
Q

How does neisseria meningitidis affect the human host?

A
  • Blocks DC activation - low CD40, CD86 and MHC Class I and II expression.
  • Antigens (capsule) with homology to self-antigen, therefore anergic T-cells.
57
Q

How does neisseria gonorrhoeae affect the human host?

A
  • Expresses Opa protein, which binds to T-cells and induces tyrosine phosphatases that ‘switch off’ key molecules involved in TCR signalling
58
Q

How does HIV affect the human host?

A
  • Upregulates PD-1 on T-cells, which antagonises TCR signalling
  • Binds to DC-SIGN to suppress DC activation via Rho-GTPases
59
Q

How does herpes simplex virus affect the human host?

A
  • Can produce proteins that binds to and inhibits TAP

- Also prevents viral peptide transfer to the ER

60
Q

How does adenovirus affect the human host?

A
  • Produce proteins that bind MHC Class I molecules

- Prevents it from leaving the ER to bind to the surface

SEM 4: Immunology (15 decks)

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