Generation of Diversity in The T Cell Repertoire

Question 1

Antigen – define

Answer 1

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

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

Question 2

Explain the immune reactions to epitopes

Answer 2

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

Question 3

Infection and vaccination usually induce what

Answer 3

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

Question 4

Which immune cells recognise and process antigen? - list

Answer 4

MONOCYTES MACROPHAGES
DENDRITIC CELLS
B-CELLS

Question 5

“Professional” Antigen-Presenting Cells (APCs): - define

Answer 5

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

Question 6

• Highly phagocytic cells - which ones and their effect

Answer 6

Macrophages + DC

Highly phagocytic cells – induce strong T-cell responses and inflammation.
Important for protection against Mycobacterium tuberculosis

Question 7

Compare specific functions of macrophages vs dendritic cells

Answer 7

• Macrophages better-equipped to kill pathogens (higher NO production); DCs
better at migrating to lymph nodes (via CCR7) and presenting antigen to Tcells

Question 8

B-CELLS - distribution

Answer 8

• Highly abundant in blood and mucosal tissues

Question 9

Macrophages + DC - distribution

Answer 9

• Rare in peripheral blood - enriched in mucosal tissues

Question 10

B-CELLS - functions

Answer 10

Receptor-mediated internalisation of antigens, as opposed to phagocytosis
• Primary function to make antibody (plasma cell) – but still very good at antigen
presentation
• Possibly main inducer of T-cell immune response to pathogens such as
Neisseria meningitidis

Question 11

Endogenous antigen processing - describe

Answer 11

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 onto 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 cells

Question 12

Macrophages function

Answer 12

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

Question 13

Is exogenous antigen processing sufficient?

Answer 13

Most cell types do not have lysosomal systems
developed as well as macrophages
BUT
Viruses can infect most cell types
A non-lysosomal mechanism to process antigens for presentation to T cells is required

Question 14

Non-lysosomal antigen processing - list types

Answer 14

ANTIGENS FROM INACTIVE VIRUSES ARE PROCESSED VIA THE EXOGENOUS PATHWAY

ANTIGENS FROM INFECTIOUS VIRUSES ARE PROCESSED VIA THE
ENDOGENOUS PATHWAY

Question 15

Immune response for inactive virus vs infectious virus

Answer 15

Inactive virus raises a weak CTL response

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

I fectious virus raises a strong CTL response

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

Most CTL recognise antigens generated via a non-lysosomal pathway

Question 16

Requirements for non-lysosomal antigen processing

Answer 16

Protein synthesis is required for non-lysosomal antigen processing

Question 17

Exogenous pathogens eliminated by

Answer 17

Antibodies and phagocyte activation by T helper cells that use antigens generated by exogenous processing

Question 18

Endogenous pathogens eliminated by

Answer 18

Killing of infected cells by CTL that use antigens generated by endogenous processing

Question 19

MHC class I - describe:

• Expressed where
• Binds what
• Presents to
• Antigens from

Answer 19

Expressed on
all nucleated
cells

Binds short
peptides (8-10
amino acids)

Presents to
CD8+ T-cells

Antigens from
the cytosol (+
crosspresentation)

Question 20

MHC class II - describe:

• Expressed where
• Binds what
• Presents to
• Antigens from

Answer 20

Expressed on
APCs and
activated T-cells

Long peptides
(typically 15-24
amino acids)

Presents to
CD4+ T-cells

Antigens from
phagosomes
and ensodomes

Question 21

The T-cell receptor - binds what

Answer 21

Binds to peptide-MHC
(pMHC) complexes –
cannot recognise peptide
alone

Question 22

The T-cell receptor - diversity and structure

Answer 22

Huge diversity – potentially
up to 1 x 1013 different TCRs

Exists in a TCR complex
with accessory molecules
such as CD3

Question 23

T cell receptor and B cell receptor - Similarities to B cell receptor/antibody:

Answer 23

Similarities to B cell receptor/antibody:
• Belongs to Ig superfamily
• Like Fab fragment of antibody
• Large diversity
• Single specificity

Question 24

T cell receptor and B cell receptor - Differences to B cell receptor/antibody:

Answer 24

• 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)

Question 25

Mechanisms which generate B-cell receptor diversity (before/after AT stim)

Answer 25

Mechanisms which generate B-cell receptor diversity Before antigen stimulation: Somatic recombination After antigen stimulation: Somatic hypermutation

Question 26

Mechanisms which generate T-cell receptor diversity | before/after AT stim

Answer 26

Mechanisms which generate T-cell receptor diversity Before antigen stimulation: Somatic recombination After antigen stimulation: None

Question 27

T cell receptor diversity - Receptor gene rearrangement takes place during

Answer 27

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

Question 28

Three signal model of T-cell activation - list + compare them

Answer 28

1. Peptide-MHC (pMHC) → 2. Co-stimulation → 3. Cytokines → Signals 1 + 2 alone will activate a naïve T-cell, but Signal 3 is also important for a strong response and also determining T-cell phenotype

Question 29

APC-T-cell interactions - describe signal one

Answer 29

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

Question 30

APC-T-cell interactions - describe signal two

Answer 30

The co-stimulatory signal (Signal Two) 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

Question 31

APC-T-cell interactions - describe signal three

Answer 31

``` 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 ```

Question 32

The immunological synapse - define

Answer 32

Complex interaction of many molecules – but simplistically Signals 1 and 2 are central, and surrounding integrins and accessory molecules help to stabilise the interaction

Question 33

Negative regulators of antigen presentation provide

Answer 33

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

Question 34

Negative regulators of antigen presentation - important molecules

Answer 34

Two important molecules – CTLA4 (Cytotoxic T-Lymphocyte-Associated Protein 4) and PD-L1 (Programmed Death-Ligand 1) are crucial for dampening the T-cell response

Question 35

T-cells - explain positive selection

Answer 35

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

Question 36

T-cells - explain negative selection

Answer 36

T-cells that bind self antigen-MHC too strongly are also deleted → NEGATIVE SELECTION • These T-cells are dangerous because they are too selfreactive

Question 37

the ‘master | controller’ of Regulatory T-cells (TREG) - define

Answer 37

In some models (STOCHASTIC MODEL), a proportion of Tcells that are strongly reactive to self-antigen will express the transcription factor FOXP3, which is the ‘master controller’ of Regulatory T-cells (TREG)

Question 38

the ‘master | controller’ of Regulatory T-cells (TREG) - function

Answer 38

Thymically-derived TREG that are reactive for self-antigen can compete with any autoreactive T-cells and secrete antiinflammatory cytokines

Question 39

IMMUNE EVASION - describe

Answer 39

Many organisms depend on human host for survival (‘obligate parasites’) – need to co-exist with the host immune system → IMMUNE EVASION

Question 40

Mycobacterium tuberculosis - effects on immune system

Answer 40

• Up-regulates PD-L1 on APCs to shut down T-cell activation • Blocks MHC Class II expression via multiple mechanisms

Question 41

Neisseria meningitidis - effects on immune system

Answer 41

• Blocks DC activation – low CD40, CD86 and MHC Class I & II expression • Antigens (capsule) with homology to selfantigen, therefore anergic T-cells

Question 42

Neisseria gonorrhoeae - effects on immune system

Answer 42

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

Question 43

HIV - effects on immune system

Answer 43

• Up-regulates PD-1 on T-cells, which antagonises TCR signalling • Binds to DC-SIGN to suppress DC activation via Rho-GTPases

Question 44

Herpes Simplex Virus (HSV) - effects on immune system

Answer 44

• Herpes Simplex Virus (HSV) • Produce protein which binds to and inhibits TAP • Prevents viral peptide transfer to ER

Question 45

Adenovirus - effects on immune system

Answer 45

``` Adenovirus • Produce protein which binds MHC class I molecule • Prevents MHC class I molecule from leaving ER ```