Immunology 6

Question 1

Describe the TCR

Answer 1

1. Short cytoplasmic tail
2. Alpha and beta components (minority have gamma and delta chains)
3. Diversity in variable region comes from VDJ recombination
4. TCR is member of Ig superfamily
5. CD3 IS A CONSTANT PART OF THE TCR

Question 2

What are the CD3 polypeptides?

DEGZ

Answer 2

Delta
Epsilon
Gamma
Zeta

Question 3

What are CD3 important for?

Answer 3

Delivering signal to T lymphocyte once antigen is recognised

CD3 has much longer cytoplasmic tails

Useful as a marker - present on all T cells

Question 4

What do CD3 tails have?

Answer 4

Motifs with Tyrosine residues

Question 5

Charged residues of the transmembrane Alpha and beta chain interact with oppositely charged residues in the transmembrane residues of CD3

Answer 5

T

Question 6

What happens when the TCR meets its antigen?

Answer 6

Tyrosine phosphorylated

Triggers other chemical cascades

Question 7

What is ITAM

Answer 7

Immunoreceptor Tyrosine-based Activation Motif

Question 8

What are the 2 major populations of T cells?

Answer 8

CD4 - MHC Class 2

CD8 - MHC Class 1

Question 9

What does binding of the co-receptors (CD4/8) to the relevant MHC achieve?

Answer 9

Increased avidity of T cell-target cell interaction

Important in signalling

Question 10

What do CD4 - T helper cells do?

Answer 10

1. Secrete cytokines
2. Recruit effector cells - activate macrophages
3. Help/activate CTL and B cell responses

Question 11

What do CD8 - Cytotoxic T lymphocyte do?

Answer 11

1. Kill target cells

2. Induce apoptosis in target cells

Question 12

Where do CD4 / CD8 bind?

Answer 12

TO THE SIDE OF THE MHC MOLECULE.

TCR BINDS TO THE ANTIGEN PRESENTED BY THE MHC

Question 13

CD8+ = viral infected cells and viral proteins. MHC CLASS 1.

Answer 13

T

Question 14

Describe CD4+ Th1.

Answer 14

1. Activates inflammatory responses.

2. Activates macrophages

Question 15

Describe CD4+ Th2.

Answer 15

1. Important in B cell response activation

Captures antigen on BCR - takes up antigen.

Antigen processed. Fragments presented on MHC Class 2.

Th2 binds and activates B cell - initiates response.

Question 16

Describe mature thymocyte production.

Answer 16

1. Progenitor cells move from bone marrow to thymus (NO CO RECEPTORS OR ANTIGEN SPECIFIC RECEPTORS AT THIS POINT).
2. Initially immature thymocytes in cortex
3. As the immature thymocytes develop, they move to the medulla - become mature thymocytes.

Question 17

What determines if the thymocyte becomes CD4+ OR CD8+?

Answer 17

Depending on the type of MHC they recognise.

CD4 - MHC 2

CD8 - MHC 1

Question 18

Describe thymocyte development in relation to the TCR.

Answer 18

B chain rearranged.

A chain rearranged.

Proper alpha-beta TCR formed

Question 19

Describe Alpha / Beta chain rearrangement in TCR.

Answer 19

1. BETA chain rearranged first. (VDJ)

2. Alpha chain rearranged second (VJ)

Question 20

Talk to me about selection of T lymphocytes.

Answer 20

Checkpoint 1

• is the new beta chain functional?
• YES = survival and development to CD4/8, a/b TCR
• NO = DEATH BY APOPTOSIS

Checkpoint 2

• Is the a/b TCR functional? Is it auto reactive?
• If useful then proceed

Checkpoint 3

• Does TCR recognise self-MHC?
• Not recognising MHC is useless
• If it binds too tightly to MHC without antigen, then it is dangerous
• Want something in between

ONLY 5% OF THYMOCYTES SURVIVE SELECTION

Question 21

Whats special about thymus epithelial cells?

Answer 21

Express both types of MHC molecule

Question 22

What are the most important genes in controlling graft rejection?

Answer 22

MHC

Question 23

What is MHC?

Answer 23

1. Group of tightly packed genes

2. Important in specific immune responses

Question 24

Describe MHC Class 1 structure.

Answer 24

2 different chains, Alpha (HEAVY) and B2-microglobulin (light).

3x Alpha chains.
1x B2-microglobulin chain

Alpha is polymorphic but B2-microglobulin chain is the same in everyone

Light chain (B2-microglobulin) binds non-covalently with Alpha chain.

B2-microglobulin is NOT TRANSMEMBRANE

Question 25

Describe MHC Class 2 structure.

Answer 25

2x Alpha chains 2x Beta chains Peptides bind between a1 and b1.

Question 26

Which MHC Molecule presents shorter chain peptides (8-10 aa long)

Answer 26

MHC Class 1

Question 27

What length does MHC Class 2 present?

Answer 27

13+ aa (longer peptides)

Question 28

Describe how peptides bind to MHC.

Answer 28

1. MHC has binding pockets. 2. In the peptide, certain positions tend to have the same amino acid, 3. This is known as a binding motif, whereby certain positions are a particular aa, other positions can be anything else. 4. So MHC presents a substantial of peptides with some things in common where characteristics are conserved.

Question 29

What is HLA?

Answer 29

Human Leukocyte Antigen., on Chromosome 6 HLA genes encode polypeptides that make up MHC molecules. HLA Class 1 has 3 types; A, B, C. HLA Class 2 has 3 types; DP, DQ, DR In class 1, only the heavy chain is encoded by the HLA. (B2-Microglobulin is encoded on a different chromosome) We are diploid, so we can have upto 6 different class 1 and class 2 molecules. HUMAN VERSION OF MHC

Question 30

MHC is polygenic and co-dominant. What is meant by this?

Answer 30

1. Several Class 1 and Class 2 loci. | 2. Maternal and paternal genes both expressed

Question 31

Which type of MHC is expressed in nearly all cells?

Answer 31

MHC Class 1 Expression varies during infection or cytokines

Question 32

Which type of MHC is expressed only in professional APCs?

Answer 32

MHC Class 2 Regulated by cytokines

Question 33

What is the most polymorphic gene in the human genome?

Answer 33

MHC

Question 34

What causes different immune responsiveness to different infections?

Answer 34

MHC is polymorphic. We have 2 MHC haplotypes (We are diploid)

Question 35

Which MHC Class is linked to autoimmune diseases?

Answer 35

MHC Class 2

Question 36

There are over 4200 HLA genes

Answer 36

T

Question 37

Are MHC haplotypes randomly distributed?

Answer 37

NO

Question 38

Define exogenous

Answer 38

Captured from the outside (e.g. phagocytosis)

Question 39

Define Endogenous

Answer 39

synthesised within cells (e.g. virus)

Question 40

Which MHC class is endogenous?

Answer 40

MHC Class 1

Question 41

Which MHC Class is exogenous?

Answer 41

MHC Class 2

Question 42

How are endogenous antigens presented?

Answer 42

Via MHC Class 1 to CD8+ T cells

Question 43

How are exogenous antigens presented?

Answer 43

Via MHC Class 2 to CD4+ T cells

Question 44

Explain endogenous antigen presentation via MHC Class 1

Answer 44

1. Viral proteins in cytoplasm are processed by proteasome 2. Peptides move into ER via TAP (Transporter associated with Antigen Processing) 3. Newly synthesised MHC Class 1 moves into ER 4. MHC Associates with chaperone proteins which aids its folding 5. Class 1 heavy chain binds with peptide and B2-microglobulin 6. All chains correctly folded. Then goes via golgi to cell surface. Awaits possible recognition by CD8 positive T cells

Question 45

Explain exogenous antigen presentation via MHC Class 2.

Answer 45

1. Proteins endocytosed and processed - peptides now in endocytic vesicles. 2. Class 2 molecules enter ER. 3. In the ER, Class 2 associates with INVARIANT chain. (iNVARIANT because not polymorphic - binds to all MHC Class 2). 4. Invariant chain has targeting signal sequence which triggers molecules to go to the Golgi 5. Invariant chain is chopped up and a small fragment remains - CLIP peptide. 6. Finally, CLIP peptide swapped for peptide derived from antigen. 7. MHC Class 2 then moves to cell surface for CD4+ T cell recognition