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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

usually refers to proteins, carbohydrates and lipids capable of binding to B-cell receptors, T-cell receptors and/or innate immune receptors

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2
Q

What is an epitope?

A

The part of an antigen molecule to which an antibody attaches itself

One antigen can have multiple epitopes

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3
Q

How do B cells produce monoclonal antibodies?

A

B cells recognise intact antigens (proteins / microbes) that havent been processed and go on to proliferate and produce → monoclonal antibodies ; produce antibody clones of the mother B cell

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4
Q

Why do T cells not produce a response to unprocessed antigens?

A

T cells don’t recognise unprocessed antigens ∴ there’s no proliferation or cytokine release
(same response with incorrect signalling)

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5
Q

What requirement must be met for T cell antigen recognition?

A

Antigens must be processed in order to be recognised by T cells
T cell requires APC interaction to produce a response

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6
Q

How are antigens processed for TCR?

A

An antigen will generate multiple peptides which are presented on APCs with MHC molecules via catabolism

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7
Q

How are antigens prepared for exogenous antigen processing?

A

Uptake mechanisms direct antigens into intracellular vesicles for exogenous antigen processing

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8
Q

What are the exogenous antigen processing mechanisms?

A

Phagocytosis

  • Fc Receptor mediated
  • Complement receptor mediated
  • Pinocytosis

Membrane Ig receptor mediated uptake

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9
Q

What are professional APCs?

A

“Professional” Antigen-Presenting Cells (APCs): Immune cells that express high levels of surface MHC Class II and can efficiently induce T-cell responses

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10
Q

What are the 2 types of APCs?

A

Myeloid cells: monocytes & macrophages

Dendritic cells (most advanced APCs)

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11
Q

Where are monocytes located?

A

Monocytes are blood circulating cells

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12
Q

Where do macrophages reside?

A

Macrophages are found in mucosal tissues and are ∴ terminally differentiated monocytes
Rare in peripheral blood - enriched in mucosal tissues

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13
Q

Compare and contrast the functions of Dendritic cells and macrophages

A

Macrophages better-equipped to kill pathogens (higher NO production)

DCs better at migrating to lymph nodes (via CCR7) and presenting antigen to T Cells

Specialised but ultimately overlapping functions

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14
Q

Where are B cells found?

A

Highly abundant in blood and mucosal tissues

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15
Q

How do B cells process antigens?

A

Receptor-mediated internalisation of antigens, as opposed to phagocytosis

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16
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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17
Q

How do B cells process antigens?

A

Contains membrane antibody on surface that can capture antigens and present it to other B cells or T cells

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18
Q

Outline how endogenous antigen processing occurs

A

Uptake: Antigens/pathogens already present in cell

Degradation: Antigens synthesised in the cytoplasm undergo limited proteolytic degradation in the cytoplasm

Antigen-MHC Complex Formation: Loading of peptide antigens on MHC class I molecules is different to the loading of MHC class II molecules

Presentation: Transport and expression of antigen-MHC complexes on the surface of cells for recognition by T cell

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19
Q

Why are macrophages so sufficient at exogenous antigen processing?

A

Macrophages have well developed lysosomal systems
Specialised for motility, phagocytosis and the introduction of particles to the lysosomal system

Most cell types do not have lysosomal systems developed as well as macrophages

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20
Q

Why is exogenous antigen processing not enough to combat viruses?

A

Viruses can infect cytosol of most cell types

A non-lysosomal mechanism to process antigens for presentation to T cells is required

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21
Q

What is the role of the proteasome in antigen processing?

A

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

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22
Q

What is the role of ER in antigen processing?

A

Peptides need access to the ER in order to be loaded onto MHC Class I molecules

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23
Q

Outline the exogenous non-lysosomal antigen processing mechanism of CD8 cells

A

Inactive virus raises a weak CTL response

The processing of antigens from inactive viruses is sensitive to lysosomotropic drugs

24
Q

Which antigens are processed via the exogenous non-lysosomal pathway?

A

Antigens from inactive viruses are processed via the exogenous pathway

25
Q

Describe the non-lysosomal antigen processing endogenous pathway

A
  1. Infectious virus raises a strong CTL response
  2. Processing of antigens from infectious viruses is NOT sensitive to lysosomotropic drugs
    Most CTL recognise antigens generated via a non-lysosomal pathway
  3. Protein synthesis is required for non-lysosomal antigen processing
26
Q

Which viruses are processed via non-lysosomal endogenous pathway?

A

Antigens from infectious viruses are processed via the endogenous pathway

27
Q

Outline how antigens are processed and presented exogenously by MHC I molecules

A
  1. Antigen is processed
  2. Cleaved into multiple peptides
  3. Presented on to MHC I on cell surface
28
Q

Outline how MHC II molecules process and present antigens endogenously

A
  1. Antigens endocytosed by macrophages / dendritic cells
  2. Sequestered into lysosomes / endosomes and processed
  3. Loaded onto MHC II molecules residing in lysosomes onto cell surface
29
Q

Outline the difference between MHC I and MHC II molecules

A

MHC I
- loaded in cytosol → CD8 T cells

MHC II
- loaded in phagolysosome → CD4 T cells

30
Q

How do antigen effector functions differ?

A

Antigens generated by endogenous and exogenous antigen processing activate different effector functions

31
Q

What are the functions of the exogenous antigen processing?

A

Eliminated by antibodies and Phagocyte activation by Th cells

32
Q

What are the antigen effector functions of endogenous pathogens?

A

Eliminated by CD8 cells

33
Q

Describe features of MHC I molecules

A
  • expressed on all nucleated cells
  • bind short peptides (8-10 a.a.)
  • present to CD8+
  • antigens from cytosol
34
Q

Describe features of MHC II molecules

A
  • expressed on APCs and activated T cells
  • Long peptides (15-24 a.a.)
  • present to CD4+
  • Antigens from phagosomes and endosomes
35
Q

Where are MHC I molecules highly expressed?

A

Epithelial cells express low density levels of MHC I whereas macrophages, T cells and B cells express high levels

36
Q

Describe the expression of MHC II molecules

A

MHC II are expressed on a much smaller subset of cells (APCs) and epithelial cells

37
Q

What are the different types of MHC I/II molecules?

A

Several types of MHC I molecules - main classes are HLA-A,B and C

MHC II are divided into HLA-DM, DO, DP etc..

These determine compatibility especially in organ transplants

38
Q

Outline how TCR and BCR are similar

A
  • Belongs to Ig superfamily
  • Like Fab fragment of antibody
  • Large diversity
  • Single specificity
39
Q

Describe how TCR differs from BCR

A
  • Lower affinity
  • Cannot be released
  • No Fc fragment, so no cellular functions
  • Single rather than two binding sites
  • B cell receptor/Ab: 5 classes
  • T cell receptor: 2 classes (ab and gd)
40
Q

What mechanisms generate BCR diversity?

A

Before antigen stimulation: Somatic recombination

After antigen stimulation: Somatic hypermutation

41
Q

|Which mechanisms generate TCR diversity?

A

Before antigen stimulation: Somatic recombination

After antigen stimulation: None

42
Q

When does TCR recombination occur?

A

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

43
Q

Outline the 3 step model of T cell activation

A

Three signal model of T-cell activation:

  1. Peptide-MHC (pMHC)
  2. Co-stimulation
  3. Cytokines

Signals 1 + 2 alone will activate a naïve T-cell, but Signal 3 important for a strong response and determining T-cell phenotype

44
Q

What is the rolw

e of cytokine release by APCs?

A

Lastly, Signal Three is formed of cytokines secreted by the APC to determine the T-cell phenotype.
• IL-12 promotes TH1 cells
• IL-4 promotes TH2 cells
• IL-23 promotes TH17 cells

These have specialised functions in dealing with pathogens

45
Q

Describe the immunological synapse structrue

A

Signals 1 and 2 are central, and surrounding integrins and accessory molecules help to stabilise the interaction

46
Q

What causes T cell signalling molecules activation?

A

Signalling molecules (kinases) are activated following ligation of the TCR with co-stimulatory molecules

47
Q

What is the role of CD4+?

A

CD4+ cells are helper T cells - recruit other cells to kill pathogens

48
Q

What is the role of CD8+?

A

CD8+ are cytotoxic T cells - directly kill infected cells

49
Q

What is the effect of CD4 activation?

A

CD4 Th1 and Th2 both produce cytokines which activate other cells

50
Q

What is the role of Th1 cells?

A

Th1 release cytokines that activate macrophages which go on to kill cellular pathogens (occurs more efficiently than without cytokines)

51
Q

What is the effect of Th2 cells?

A

Th2 cells release cytokines that may activate B cells that produce antibodies. The antibodies will neutralise circulating viruses or prevent bacterial colonisation

52
Q

Which molecules are responsible for inactivating T cells?

A

CTLA4 (Cytotoxic T-Lymphocyte-Associated Protein 4)

PD-L1 (Programmed Death-Ligand 1) are crucial for dampening the T-cell response

53
Q

How does PD-L1 inactivate T cells?

A

PD-1 expressed on T cells is activated by PD-L1 (programmed death ligand 1) which blocks TCR activation through multiple signalling pathways

54
Q

How does CTLA4 mediate T cell activation?

A

CTLA-4 molecule competitively acts on the costimulatory CD28 molecule binding site

55
Q

Where do self antigens arise form?

A

T-cells arise from the thymus, which is a ‘school’ for T-cells
T-cells are exposed to self-antigens and tested for reactivity

56
Q

Describe the positive selection for self antigens

A

T-cells that can’t bind self antigen-MHC are deleted → POSITIVE SELECTION

• These T-cells are useless because they won’t protect against pathogens

57
Q

What is negative selection of self antigens?

A

T-cells that bind self antigen-MHC too strongly are also deleted → NEGATIVE SELECTION

• These T-cells are dangerous because they are too self reactive

Immunology (14 decks)

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