T and B cells : MHC

Question 1

Where are T cells derived from ?

Answer 1

T cells derive from bone marrow stem cells.

Question 2

Where do T cells mature ?

Answer 2

T cell precursor cells arrive in the thymus and spend 7-21 days undergoing differentiation and proliferation into a mature, antigen naive, phenotype.

Question 3

Describe the fates of T cells in the thymus

Answer 3

2-4% of thymocytes leave the thymus as mature T cells to populate the lymph nodes.

Over 95% of thymocytes die in the thymus.

Question 4

State some examples of thymocytes

Answer 4

CD4
CD8

Question 5

Describe educating T cells

Answer 5

Small double + thymocytes initially express low levels of receptor they use to recognise antigen, TcR

Most of the TcR won’t recognise MHC molecules, so the T cells die, due to a lack of ‘positive selection’

The T cells that do recognise the MHC molecules, mature and express high levels of TcR

They then lose either CD4 or CD8 to become single + cells.

During this stage the T cells also undergo ‘negative selection’ to eliminate T cells that see MHC with high affinity.

Question 6

HLA

Answer 6

Human Leukocyte Antigens

• found in humans only

Question 7

MHC

Answer 7

Major Histocompatibility Complex

• umbrella term

Question 8

Function of negative selection

Answer 8

Eliminates T cells that see your MHC molecules with a high affinity

i.e. which could become auto-reactive T cells

(T cells which bind too strongly can be seen as auto-reactive)

Question 9

Function of educating T cells

Answer 9

A process of + and - selection to define and select a suite of T cells which recognise your own MHC molecules with the right affinity.

But not so much that the T cells become activated all the time.

These cells are released into the periphery.

Question 10

Describe T cells which have been educated

Answer 10

Finely tuned to ignore MHC molecules most of the time.

If there is an odd MHC molecule which is showing a bit of a virus/pathogen/ present in tumour cells, then this is enough to activate the T cell and push it over the level.

Question 11

What does thymic education result in ?

Answer 11

Results in the release into the periphery of cells that are restricted to recognising your own MHC.

Question 12

Describe the T cell receptor

Answer 12

Shares sequence similarities with immunoglobulins, but it is a bit different.

2 polypeptide chains, membrane bound, each with a V and C domain.

Question 13

What is the T cell receptor binding site similar to ?

Answer 13

TcR binding site is very similar to an antibody.

Both are members of the Immunoglobulin superfamily.

Question 14

How do you generate diversity in TcR’s ?

Answer 14

TcR undergo chromosomal rearrangement, similar to antibody genes.

Question 15

Key feature of TcR

Answer 15

Only ever recognises an antigen when it is bound by an MHC molecule.

• TcR antigen recognition is MHC restricted

Question 15

Function of MHC molecules

Answer 15

Take parts of proteins from inside your cell and show them on the cell surface.

• Protein antigen in cell
• Antigen processing by breakdown of protein
• Presentation of peptides by MHC molecules

(MHC molecules bind peptides)

Question 16

Where is HLA found ?

Answer 16

HLA is expressed on every single cell in the body, except they are relatively low in the brain and neurone tissue.

RBCs don’t express HLA, but platelets do.

Question 17

State the 2 types of MHC molecules

Answer 17

MHC class 1
MHC class 2

Question 18

Where is MHC class 1 expressed ?

Answer 18

Expressed on almost every cell in your body, though at low levels in some (e.g. CNS)

Question 19

Describe structure of MHC class 1

Answer 19

2 chains
- Heavy chain
- Small Beta2-microglobulin

Upper surface forms a groove in which small 9-11 amino acid peptides sit.

Question 20

Where is MHC class 2 expressed ?

Answer 20

Expression more limited to specialised antigen presenting cells and immune cells.

e.g. Macrophages, dendritic cells, B and T cells

Question 21

Describe the structure of MHC class 2

Answer 21

2 chains
- Alpha and Beta, both membrane bound

Upper surface forms a groove into which longer peptides, over 20 amino acids sits.

Question 22

Describe MHC molecule recognition

Answer 22

The 2 MHC molecule types are seen by different T cells.

MHC class 1 - CD8 T cells
MHC class 2 - CD4 T cells

Question 22

What is the difference between a CD4 T cell and a CD8 T cell ?

Answer 22

MHC class 1 & the peptide - CD8+ T cells
(can occur on any cell in the body)

MHC class 2 & the peptide - CD4+ T cells
(restricted to immune interactions)

Question 23

MHC class 1 VS MHC class 2

Answer 23

Class 1: shorter peptide groove

Class 2: longer peptide groove, groove is more shallow

Question 24

Where do MHC class 1 molecules pick up and meet peptides from ?

Answer 24

MHC class 1 - picks up peptides mostly derived from the internal contents of your cells (e.g. cytoplasm and nucleus)

MHC class 1 - meets peptides in the ER

Question 25

Where do MHC class 2 molecules pick up and meet peptides from ?

Answer 25

MHC class 2 - picks up peptides derived from external sources (i.e. outside your cells)

MHC class 2 molecules meet peptides in endosomes.

Question 26

State some differences between the MHC classes

Answer 26

MHC class 1 expressed by most cells in the body.
MHC class 2 expression is more limited to immune response.

MHC class 1 recognised by CD8 T cells
MHC class 2 recognised by CD4 T cells

MHC class 1 picks up peptides from internal contents of cells.
MHC class 2 picks up cells from external sources - outside the cell.

MHC class 1 meets peptides in the ER
MHC class 2 meets peptides in endosomes.

Question 27

CD8 T cells

Answer 27

Cytotoxic T cells

Question 28

CD4 T cells

Answer 28

Helper T cells

Question 29

Function of interaction with MHC class 2

Answer 29

Interaction of T cells with MHC class 2 drives the secretion of cytokines to help boost other immune responses.

Question 30

Function of interaction with MHC class 1

Answer 30

Interaction generates killer T cells

Question 31

Describe MHC class 1 meeting peptides

Answer 31

Antigen processing to peptides in proteasome.

Peptide transport into the ER.

Peptide binding by MHC class 1.

MHC class 1 presents peptide at cell surface.

Question 31

Describe MHC class 2 meeting peptides

Answer 31

Peptide production in phago-lysosome

Peptide binding by MHC class 2

MHC class 2 presents peptide at cell surface.

Question 32

Feature of HLA class 1 and 2 molecules

Answer 32

They are incredibly diverse

• MHC molecules are highly polymorphic

Question 33

Where are polymorphisms located ?

Answer 33

Located in the peptide-binding groove

Each different MHC molecule will present different peptides to the immune system.

Question 34

State some examples of diseases with an HLA association.

Answer 34

Autoimmunity
- Ankylosing spondylitis

(association with class 2 MHC)
- Multiple sclerosis
- Diabetes
- Rheumatoid arthritis

Question 35

What is a major factor in graft rejection in transplantation ?

Answer 35

MHC disparity

T cells are educated to see your own MHC molecules, anyone else’s are similar but different enough to cause a response.

Question 36

What can improve graft survival rates ?

Answer 36

MHC matching is crucial.

Even if a full match is obtained, you have enough different peptides to trigger a slow graft rejection, so immunosuppression is still required.

Question 37

Cancer

Answer 37

A multitude of tumour lines from the different stages of B and T cell development.

Question 38

Hodgkins disease

Answer 38

B cell lineage
Large cells

Question 39

Superantigens

Answer 39

Some bacteria and viruses produce proteins that interfere with the interaction of TcR and MHC, stimulating large numbers of T cells.

e.g. Toxic shock syndrome

Question 40

DiGeorges syndrome

Answer 40

Failure to develop thymus epithelia, few T cells are produced.

Question 41

Severe combined immunodeficiency

Answer 41

Loss of the T cell compartment leads to loss of ability to produce cell mediated and antibody response.

Question 42

Bare lymphocyte syndrome

Answer 42

Can affect Class 2 and 1

Class 2 deficient patients still produce CD8 T cells, but have SCID because CD4 cells control immune response.

Class 1 deficient patients have few CD8 cells but manage to have reasonable immune responses against most pathogens.