Introduction to T Cells and the T Cell Receptor

Question 1

What do T cells do?

Answer 1

Attack infected cells

Question 2

What do B cells do?

Answer 2

Attack invaders outside the cells

Question 3

How do T cells recognise pathogens from outside infected cells?

Answer 3

Antigen proteolysis inside the infected cell
Peptides presented on cell surface by MHC class 1 or 2 molecules

Question 4

What recognises the MHC-peptide combination?

Answer 4

TCR

Question 5

What happens after recoginition?

Answer 5

Activation of signalling processes inside the T cell leading to functional responses

Question 6

What is the Listeria model?

Answer 6

From a study done in 1960s, used pathogen called listeria (lives inside macrophages) to investigate specific immunity
Involved adoptive transfer and in vitro reconstitution experiment

Question 7

What is adoptive transfer?

Answer 7

Transfer of immune cells from an animal that has recovered from listeria to another animal not been infected yet to protect them from listeria
Adoptive transfer with serum failed to transfer specific immunity but T cell transfer was successful at protecting

Question 8

What is in vitro reconstitution?

Answer 8

Macrophages infected with listeria - they die
If macrophages become activated by the infection and then T cells are added then very effective killing of listeria occurs
However, if macrophages not activated (by second signal) then killing of listeria not effective
Means that T cells work with something to kill pathogens

Question 9

How do T cells activate macrophages?

Answer 9

Engagement of TCR with MHC on macrophage, activating effector T cell
Binding of CD40L and CD40
Release of IFN gamma which activated the macrophage
Secretion of cytokines, increased expression of MHC and costimulators, killing of phagocytosed bacteria

Question 10

What is the nature of the cell-mediated immune response dependent on?

Answer 10

The pathogen

Question 11

What does killing of listeria require?

Answer 11

T cells
Macrophages

Question 12

What does killing of parasites require?

Answer 12

IgE
Eosinophils
Mast cells

Question 13

What does killing of virally infected cells require?

Answer 13

Only T cells

Question 14

What are the types of T cells?

Answer 14

Cytotoxic
Helper
Suppressor

Question 15

What is MHC restriction?

Answer 15

T cells have to recognise both the peptide and MHC allele presenting it

Question 16

Under what circumstances will the T cells recognise the antigens?

Answer 16

If it is presented by the self MHC

Question 17

What would happen without the need for dual antigen/MHC recognition?

Answer 17

Toxic shock syndrome eg. caused by the staphylococcal syndrome toxin-1 which acts as a superantigen

Question 18

What does the superantigen do?

Answer 18

Binds directly to both MHC class 2 and TCR, triggering multiple T cells to prod cytokines

Question 19

Why do TCRs have a large range of specifities?

Answer 19

Highly variable amino acid sequence of the variable (Ag-binding) region

Question 20

What is the structure of the TCR?

Answer 20

Highly variable antigen-binding domains attached to constant regions
TCR has only 1 binding site
TCRs do not bind native antigens but only processed peptides bound in the cleft of MHC-encoded proteins

Question 21

What generates diversity?

Answer 21

Rearrangement of TCR genes (like Igs)

Question 22

Where does TCR rearrangement occur?

Answer 22

In the thymus

Question 23

Why is junctional diversity prominent in TCR genes?

Answer 23

Insertion of non-coded bases and variation of joining site is more important in TCR than in Igs because there is no somatic hypermutation in TCR (Igs will continue to refine the antibody; does not happen in T cells)
Results in diverse a.a sequences in CDR3 loops which make contact with presented peptide

Question 24

What are T cells derived from?

Answer 24

Haematopoietic stem cells in BM

Question 25

Where do HSCs migrate to?

Answer 25

Thymus

Question 26

What do T cells become?

Answer 26

CD4+ or CD8+

Question 27

Where do naive T cells migrate to?

Answer 27

Secondary lymphoid tissue

Question 28

What do naive T cells interact with?

Answer 28

Peptides presented on MHC molecules by APCs

Question 29

What occurs upon productive interaction with a T cell?

Answer 29

Clonal selection Amplification of T cell

Question 30

What happens to selected and amplified T cells?

Answer 30

Leave the lymph nodes and target infected tissues

Question 31

Where is the T cell repertoire selected and how ?

Answer 31

In the thymus T-cell precursors travel from BM to develop in the thymus

Question 32

What are double negative T cells?

Answer 32

Newly arrived cells in the thymus (early thymic progenitor cells) CD4- CD8- Do not express TCR

Question 33

What happens to the double negative cells?

Answer 33

Upregulate CD25 (IL-2 receptor) and RAG1 & RAG2 Rearrange TCR-beta locus

Question 34

What happens after rearrangement of TCR-beta?

Answer 34

T cells express an invariant alpha chain called pre-T alpha alongside the TCR beta gene If rearranged beta chain successfully pairs with the invariant alpha chain, signals are produced, ceasing rearrangement of beta chain Pre-TCR forms and cells undergo a round of proliferation Rearrangement of TCR-alpha locus Pre-TCR signals the cells to transcribe the genes for CD4 and CD8 CD4+ CD8+ cells produced = double positive

Question 35

What are the 3 classes of TCRs produced?

Answer 35

Potentially useful in interacting with foreign pathogens Do not interact with anything Potentially harmful, react with self antigens

Question 36

What happens to the double positive cells?

Answer 36

Migrate deep into thymic cortex and are presented with self-antigens Self antigens expressed by thymic cortical epithelial cells (CTECs) on MHC molecules on cell surface

Question 37

Which cells receive survival signals?

Answer 37

Only those that interact with MHC-I or MHC-II

Question 38

When is the TCR first expressed for AB T cells?

Answer 38

During development in the thymus

Question 39

What is the purpose of negative T cell selection ?

Answer 39

Elimination of self-reactive cells

Question 40

What is the purpose of positive selection?

Answer 40

To select for cells with TCRs capable of interacting with self-MHC

Question 41

What is death by neglect?

Answer 41

Cells that do not interact strongly enough with MHC peptide complexes will die (no survival signal) Ensures that selected T cells will have MHC affinity that will serve useful functions in the body

Question 42

What happens to DP cells that interact with MHC II?

Answer 42

Become CD4+ by downregulation of CD8 surface receptors

Question 43

Where does negative selection occur?

Answer 43

In the thymic medulla thymocytes are presented with self-antigen on MHC of medullary thymic epithelial cells (mTECs)

Question 44

What happens to thymocytes that interact too strongly with the self-antigen?

Answer 44

Receive apoptotic signal leading to cell death Some are selected to become Treg cells

Question 45

Under what circumstances does negative selection work?

Answer 45

If it can eliminate self antigens expressed in all tissues - but the thymus is a specialised tissue so cannot do this Solved by mTECs expressing transcription factor AIRE - allows promiscuous expression of self antigens from all tissues of the body on MHC I

Question 46

What problem remains regarding negative selection?

Answer 46

How to negatively select T cells that recognise self antigens expressed on MHC II Solved by thymic dendritic cells which can phagocytose mTECs - allowing for presentation of self-antigens on MHC II

Question 47

What attracts naive T cells into the lymph nodes?

Answer 47

Chemokine receptor CCR7 on T cell recognises CCL21 prod by specialised blood vessels called high endothelial venules (HEV) CCR7 also recognises CCL19 prod by DCs in the lymph node

Question 48

How do T cells enter the lymph node?

Answer 48

L selectin on naive T cell induces rolling Chemokine CCL21 recognition activates integrins to enhance their binding T cell continues to follow chemokine gradient into lymph node

Question 49

What happens to T cells that do not encounter their antigen?

Answer 49

Re-enter blood and continue circulating

Question 50

How are effector T cells guided to sites of infection?

Answer 50

By chemokines and newly expressed adhesion molecules

Question 51

What happens when naive T cells become effector T cells?

Answer 51

Cease production of L-selectin Express VLA-4, which recognises VCAM-1 VCAM-1 found on activated vascular endothelium when inflammation is triggered

Question 52

How do T cells find their targets?

Answer 52

By cell adhesion Non specific adhesion proteins allow initial binding to potential targets If target has correct antigen/MHC combination, TCR signalling occurs Induces conformational change in adhesion proteins which strengthens binding Focused release of effector molecule

Question 53

Describe gamma delta T cells

Answer 53

2 distinct chains forming gamma delta heterodimer Less variable than convention ab TCR Together with CD3 may play a role in innate immunity Found in peripheral sites (skin, lung, intestine, liver)