5 TCR

Question 1

difference between TCR and antibody

Answer 1

T cell receptor is always membrane bound, but antibody can be soluble and secreted, or membrane bound to B cell to make the BCR

Question 2

how do TCR have a very large range of specificities?

Answer 2

Like Ig, this is due to highly variable amino acid sequence of the variable (antigen-binding) region.

Question 3

There are 3 main types of T-cell:

Answer 3

Cytotoxic T-cells (TC), Helper T-cells (TH), Regulatory T-cells (Tregs)

Question 4

how do antibodies recognise cytotoxic T cells?

Answer 4

surface protein CD8

Question 5

how do antibodies recognise helper T cells?

Answer 5

cell surface protein CD4

Question 6

function of helper T cells?

Answer 6

Helper T-cells will secrete cytokines and activate the immune response when presented with an antigen from an MHC class II when they bind with CD4+.

Helper T-cells activate other cells, e.g. B cells and macrophages , by cell-cell contact and secreting cytokines:

TH1 cells secrete cytokines, e.g. interferon-g, which mainly activate virally infected cells, macrophages and other T-cells.
TH2 cells secrete cytokines, e.g. Interleukins-4,5,10 and 13, that mainly activate B-cells.
TH17 cells produce proinflammatory IL-17, IL-17F which induces cytokine production by epithelia.

Question 7

TH1 cell role

Answer 7

TH1 cells secrete cytokines, e.g. interferon-g, which mainly activate virally infected cells, macrophages and other T-cells.

Question 8

TH2 cell role

Answer 8

TH2 cells secrete cytokines, e.g. Interleukins-4,5,10 and 13, that mainly activate B-cells.

Question 9

TH17 cell role

Answer 9

TH17 cells produce proinflammatory IL-17, IL-17F which induces cytokine production by epithelia.

Question 10

function of regulatory T-cells (Tregs)

Answer 10

They act dominantly to suppress the immune response and induce tolerance – evidence for this comes from mouse studies where mice that do not have Tregs spontaneously developed autoimmune disease.

Question 11

what surface proteins do Tregs display?

Answer 11

Mainly display CD4 and often CD25.

Question 12

why is the TCR a bit similar to Ig (structure-wise)?

Answer 12

TCRs and immunoglobulins share a common evolutionary origin as they both have highly variable antigen-binding domains attached to constant regions.

TCRs and immunoglobulins both belong, together with the MHC-encoded proteins, to the immunoglobulin super-family of proteins

Question 13

imp differences between TCR and Ig?

Answer 13

TCRs do not bind to native antigens but only to processed (cleaved) peptides (7-20 amino acids) bound in the cleft of MHC-encoded proteins by APC’s.

Question 14

Do Helper T-cells bind to MHC Class I or MHC Class II?

Answer 14

Helper T-cells are CD4+ and bind to MHC Class II.

Question 15

Do Cytotoxic T-cells bind to MHC Class I or MHC Class II?

Answer 15

Cytotoxic T-cells are mostly CD8+ and bind to MHC Class I

Question 16

MHC binding

Answer 16

Cytotoxic T-cells are mostly CD8+ and bind to MHC Class I.

Helper T-cells are CD4+ and bind to MHC Class II.
Treg-cells also CD4+.

Mechanism of binding to MHC is the same but the consequences of binding to either class is different.

Cytotoxic T-cells will destroy the cell which presents the antigen in its MHC (class I) when they bind with CD8+.

Helper T-cells will secrete cytokines and activate the immune response when presented with an antigen from an MHC class II when they bind with CD4+.

These responses must be kept separate so an inappropriate response is not produced.

Question 17

The T-cell Receptor (TCR) structure

Answer 17

TCRs are ab heterodimers, each about 280 amino acids. The TCR has 2 domains for both the alpha and beta chains - a variable region and a constant region. The alpha and beta chains have carbohydrate side chains.

The consequence of having highly variable binding sites is that the correct antigen is very rarely met.

Each of the chains has 2 Ig-like domains, variable and constant.

Antigen-binding loops (complementarity-determining regions-CDRs) are shown in red – this is where there is great variability in the amino acid sequence.

TCRs are associated with a complex called CD3.
Cell signalling occurs in the transmembrane region via the CD3 complex - involved in activating the cell for differentiation/proliferation.

Polypeptides are 27-34 kd, plus carbohydrate modifications.

Distinct T-cell populations carry a different receptor- the gamma/delta heterodimer. These gamma-delta receptors do not interact with MHC - some at least bind to phospholipid antigens.

Question 18

what do T cells recognise?

Answer 18

foreign peptide presented by the MHC proteins. The TCR interacts both with antigenic peptides and the MHC proteins presenting it.

Each T-cell will not bind to any other cell that does not have the specific peptide for it’s receptors.

This phenomenon is associated with MHC restriction - a TCR will only bind to a peptide presented by self-MHC.

Other interactions (cell-cell adhesions and co-stimulatory proteins) are not sufficient on their own for a T cell to interact with a dendritic cell but at the same time, the MHC interaction is not sufficient on its own to elicit a strong enough interaction.

Question 19

MHC stands for…

Answer 19

Major Histocompatibility Complex

Question 20

what forms a 3 way complex?

Answer 20

TCR, Antigen and MHC Protein

Question 21

how is the MHC cleft created?

Answer 21

The MHC cleft is created by the two alpha-helices. The peptide binds within that cleft, interacting with the base and the alpha helix itself. The TCRs interact with both the peptide and the MHC.

Both alpha and beta chain region 2 are not interacting with the peptide – they are interacting with the MHC. As these regions are highly variable, this means that a TCR can be restricted to a specific MHC.

Question 22

Rearrangement of TCR Genes Generates….

Answer 22

Diversity (same as Ig’s):

TCR genes are encoded in separate segments (Vs, Js and a C for TCRα and Vs Js, Ds and Cs for TCRβ).

Any one of the variable regions in alpha can join to one of the joining regions.

Any one of the variable regions in beta can join to any one of the joining or diversity regions.

This enables the possibility of a large variety of combinations.

No complete gene exists in the germline of the TCR. You can only generate a TCR when you join the regions together.

Question 23

How does peptide binding to MHC class I and II differ?

Answer 23

Peptides bind to MHC Class I mainly by their ends. “Anchor residues” within the peptide also important in conferring specificity. Groove is formed by the α1 and α2 domains of the MHC class I heavy chain.

Peptides bind to MHC Class II by interactions along the length of the groove, so longer peptides can be bound.
Groove is formed by the α1 domain and β1 domain.

Question 24

do MHC proteins bind to a range of peptides?

Answer 24

MHC proteins will bind to a range of peptides

- in contrast to the TCR and Ig, which have very fine antigen specificity

Question 25

when are TCR genes rearranged?

Answer 25

during T-Lymphocyte Development in the Thymus

Question 26

what does gene rearrangement require?

Answer 26

requires RAG genes and signalling sequences at the appropriate sites to allow the looping out or inversion of intervening DNA to bring single V, D, J and C’s together.