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Immunology > Generation of diversity in the T cell repertoire > Flashcards

Generation of diversity in the T cell repertoire Flashcards

1
Q

What is an antigen?

A

A combination of ‘antibody’ and ‘generate.’ Any molecule that can bind specifically to an antibody

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2
Q

What does an antigen induce?

A

○ Will induce an immune response in host

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3
Q

What do adaptive immune reactions occur to?

A

• Adaptive immune reactions occur to specific epitopes (portions of the antigen) as opposed to the entire antigen itself

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4
Q

What does an infection or vaccination induce?

A

Infection and vaccination usually induce polyclonal T- and B-cell responses

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5
Q

What can epitopes be?

A

• Epitope can be small peptide

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6
Q

What is an epitope the target for?

A

• Epitope is the target for the antibodies and MHC and TCRs

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7
Q

Where can multiple epitopes be recognised?

A

• Multiple epitopes can be recognised on a single antigen

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8
Q

What form of antigens to T cells not recognise?

A

T cells do not recognize native antigens

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9
Q

What do B cells typically recognise and what happens to this B cell?

A
  • B cells will typically recognise unprocessed antigens/intact antigens
  • This B cell will proliferate and make clones which will all produce antibodies just like the original B cell – CLONAL EXPANSION
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10
Q

What do T cells not respond to?

A

○ T cells do not respond to an unprocessed antigen

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11
Q

What needs to be seen in order for T cells to be activated?

A

• Need to see antigenic peptides for T cells to be activated

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12
Q

What do antigens become presented through?

A

• Antigens become presented through phagocytosis or controlled membrane uptake via receptors and antibodies

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13
Q

What are antigen-presenting cells?

A

Immune cells that express high levels of surface MHC Class II and can efficiently induce T-cell responses

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14
Q

Where are monocytes found?

A

○ Monocytes are found in blood

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15
Q

Where are macrophages found?

A

○ Macrophages are found in tissue – are not in circulation

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16
Q

What are macrophages?

A

○ Macrophages are terminally differentiated monocytes

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17
Q

What are dendritic cells better at processing?

A

○ DCs are better at processing antigens and macrophages are better at phagocytosis

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18
Q

Where are macrophages and dendritic cells enriched in?

A

Enriched in mucosal tissues

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19
Q

What do highly phagocytic cells induce and what is it important for protection against?

A

Induce strong T-cell responses and inflammation.

Important for protection against Mycobacterium tuberculosis

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20
Q

What are macrophages good at?

A

equipped to kill pathogens

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21
Q

What are dendritic cells better at?

A

DCs are better at migrating to lymph nodes (via CCR7) and presenting antigen to T- cells

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22
Q

What are dendritics of dendritic cells?

A

DCs have dendrites that are extensions of the cell membrane to increase cell surface and interaction with the environment

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23
Q

What is mucosal tissue?

A

tissue in direct contact with external environment

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24
Q

What are B cells highly abundant in?

A

○ Highly abundant in blood and mucosal tissues

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25
Q

What is the primary function of B cells?

A

○ Primary function to make antibody (plasma cell) – but still very good at antigen presentation

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26
Q

What are B cells possibly main inducers of?

A

○ Possibly main inducer of T-cell immune response to pathogens

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27
Q

Steps in endogenous antigen processing

A
  1. Uptake
    ○ Antigens/pathogens already present in the cell
  2. Degradation
    ○ Antigens synthesised in the cytoplasm undergo limited proteolytic degradation in the cytoplasm
    ○ Needs to be cleaved to smaller peptides
  3. Antigen-MHC complex formation
    ○ Loading of peptide antigens onto MHC class I molecules is different to the loading of MHC class II molecules
  4. Presentation
    ○ Transport and expression of antigen-MHC complexes on the surface of cells for recognition by T cells
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28
Q

IS EXOGENOUS ANTIGEN PROCESSING SUFFICIENT?

A

Macrophages have well developed lysosomal systems which most other cell types don’t. This means non-lysosomal mechanism to process antigens for presentation to T cells is required.

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29
Q

What are lysosomal systems specialised for?

A

○ Specialised for motility, phagocytosis and the introduction of particles to the lysosomal system

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30
Q

Where are peptide antigens produced and what are they seperated from?

A

Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I

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31
Q

How are antigens from inactive viruses processed?

A

• Antigens from inactive viruses are processed via exogenous pathways

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32
Q

What response does an inactive virus raise?

A

• Inactive virus raises a weak CTL response

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33
Q

What is the processing of antigens from inactive viruses sensitive to?

A

• The processing of antigens from inactive viruses is sensitive to lysosomotrophic drugs

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34
Q

What response do infectious viruses raise?

A

• Infectious virus raises a strong CTL response

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35
Q

What is the processing of antigens from infectious viruses not sensitive to?

A

• The processing of antigens from infectious viruses is NOT sensitive to lysosomotrophic drugs

36
Q

What do most CTL recognise and via what pathway?

A

• Most CTL recognise antigens generated via a non-lysosomal pathway

37
Q

What is required for non-lysosomal antigen processing?

A

• Protein synthesis is required for non-lysosomal antigen processing

38
Q

What are antigens from infectious viruses processed via?

A

• Antigens from infectious viruses are processed via the endogenous pathway

39
Q

Exogenous pathway of antigen processing and presentation?

A

○ Antigen is processed, cleaved and presented on MHC I

40
Q

Endosomal pathway of antigen processing and presentation

A 
○ Antigens are endocytosed
○ Sequestered to lysosomes/endosomes
○ Loaded onto MHC class II which are in the lysosome unlike MHC class I which are in the cytosol
41
Q

Where are antigens loaded in MHC II?

A

In MHC II, its loaded in the phagolysosome

42
Q

Where are antigens loaded in MHC I?

A

In MHC I, it’s in the cytosol

43
Q

What does MHC II activate and need assistance from?

A

○ MHC II activate CD4 T cell and also needs assistance from CD8

44
Q

How many type of MHC are their?

A

2 types

45
Q

What MHC do all cells in the body express?

A

• All cells in body express MHC class I

46
Q

What are MHC I expressed on?

A

Expressed on all nucleated cells

47
Q

What are MHC II expressed on?

A

Expressed on APCsand activated T-cells

48
Q

What does MHC I bind?

A

Binds short peptides (8-10amino acids)

49
Q

What does MHC II bind?

A

Long peptides (typically 15-24amino acids)

50
Q

What does MHC I present to?

A

Presents to CD8+T-cells

51
Q

What does MHC II present to?

A

Presents to CD4+T-cells

52
Q

What does TCR bind and what does it need to find?

A

○ Binds to peptide-MHC (pMHC) complexes – cannot recognise peptide alone
○ TCR needs to find peptide groove on APC and recognise peptide in the complex with the MHC

53
Q

T cell similarities to B cell receptor/antibody

A

○ Belongs to Ig superfamily
○ Fab like fragment of antibody
§ T cell has peptide groove instead of antigen binding site but is structurally similar
○ Large diversity
○ Single specificity
§ One TCR will only bind one peptide

54
Q

T cell differences to B cell receptor/antibody

A

○ Antibody has very high affinity to antigens: 107-109
§ TCR has lower affinity – kd = 105
○ TCR cannot be released
§ Antibodies are first produced on surface of cell and then eventually released to become circulating antibodies
§ TCR remains on cell surface all the time
○ TCR does not have Fc fragment, so no cellular functions
○ TCR has single bind site rather than two binding sites
○ B cell receptor/Ab: 5 classes
○ T cell receptor: 2 classes (ab and gd)

55
Q

What are the mechanisms which generate B-cell receptor diversity before and after antigen stimulation?

A

○ Before antigen stimulation: Somatic recombination

○ After antigen stimulation: Somatic hypermutation

56
Q

What are the mechanisms which generate T-cell receptor diversity before and after antigen stimulation?

A

○ Before antigen stimulation: Somatic recombination

○ After antigen stimulation: None

57
Q

What does receptor gene rearrangement take place during?

A

Receptor gene rearrangement takes place during T-cell development in thymus

58
Q

What are the three signal mode of T cell activation?

A
  1. Peptide MHC
  2. Co-stimulaiton
  3. Cytokines
59
Q

How is the Peptide MHC signal mode of T cell activation delivered?

A

The main signal (signal 1) is delivered from the APC by a peptide-MHC complex to the TCR

60
Q

How is the co-stimulation of T cell activation delivered?

A

The co-stimulatory signal (Signal 2) is delivered from the APC by germline-encoded accessory receptors such as the ‘B7 family’ (CD80 and CD86) – although many of these receptors are not fully characterised or understood

61
Q

What is the cytokine signal mode of T cell activation formed of?

A

Lastly, Signal Three is formed of cytokines secreted by the APC to determine the T-cell phenotype

62
Q

What does cytokine IL-12 promote?

A

IL-12 promotes TH1 cells

63
Q

What does cytokine IL-4 promote?

A

IL-4 promotes TH2 cells

64
Q

What does cytokine IL-23 promote?

A

IL-23 promotes TH17 cells

65
Q

What does peptide MHC and co-stimulation activate?

A

Signal 1 and 2 alone will activate naïve T cel

66
Q

What is cytokine signal not needed for and what does it do?

A

Signal 3 not needed for initiation but amplifies the response

67
Q

What happens along the immunological synapse?

A

• Interaction of TCR with peptide-MHC complex happens first
○ Not very high affinity
○ Interaction is therefore very short lived unless additional interactions occur
§ Costimulatory molecules such as CD80 and CD86 interact with their T cell partners to strengthen the interaction
§ Keep the cells in contact for long enough so that the information can be exchanged along the synapse
• Complex interaction of many molecules – but simplistically Signals 1 and 2 are central, and surrounding integrins and accessory molecules help to stabilise the interaction

68
Q

What are most of the CD4 cells and what do they help with?

A

Most of the CD4 cells are helper T cells so help cells kill pathogens

69
Q

What do CD4 cells produce?

A

Produce cytokines which activate other cells

70
Q

What do TH2 produce and what may they activate?

A

○ TH2 produces other types of cytokines which may activate b cells that produce antibodies

71
Q

What are cells that express CD8?

A

Cells that express CD8 are cytotoxic cells so directly kill infected cells

72
Q

What do negative regulators of antigen presentation provide?

A

Negative regulators of antigen presentation provide an ‘immune checkpoint’ to limit T-cell activation

73
Q

What does the immune response need to do once a virus has been dealt with?

A

Once a virus has been dealt with, the immune response needs to subside and only a memory T cell should remain in circulation and reactivate upon second exposure

74
Q

What is Pd-1 expressed on?

A

Pd-1 is expressed on T cells

75
Q

What are Pd-1 on T cells be activated by?

A

Can be activated by PD-L1

76
Q

What happens once Pd-1 on T cells is activated?

A

When activated, blocks TCR activation by causing SHP-2 to dephosphorylate TCR signalling molecules

77
Q

What does CTLA-4 act on and to do what?

A

CTLA-4 acts on costimulatory molecules to block them and therefore block TCR activation

78
Q

What does CTLA-4 compete with for APC attention?

A

CTLA-4 competes with CD28 for APC attention

79
Q

What do T cells arise from?

A

T-cells arise from the thymus

80
Q

What are T cells exposed to and tested for?

A

T-cells are exposed to self-antigens and tested for reactivity

81
Q

What happens to T cells that bind self-antigen MHC too strongly and what is it done through?

A

○ All T cells that bind self-antigen-MHC too strongly are deleted from the repertoire as these cells are harmful as they are too self-reactive
○ Done through negative selection and induction of apoptosis

82
Q

What happens to T cells that cant bind and what is it done through?

A
  • T-cells that can’t bind self antigen-MHC are also deleted

* Done through positive selection

83
Q

What transcription factor is expressed when a proportion of T cells are strongly reactive to self-antigen and what is it the master controller of?

A

○ A proportion of T- cells that are strongly reactive to self-antigen will express the transcription factor FOXP3, which is the ‘master controller’ of Regulatory T-cells (TREG)
• These cells will regulate any potential self-reactive T cells by inducing apoptosis or deletion

84
Q

What does HSV produce and prevent?

A

○ Produce protein which binds to and inhibits TAP

○ Prevents viral peptide transfer to ER

85
Q

What does adenovirus produce and prevent?

A 
○ Produce protein which binds MHC class I molecule
○ Prevents MHC class I molecule from leaving ER

Immunology (8 decks)

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