B and T Cells and MHC

Question 1

How are T cells derived?

Answer 1

T cells derive from bone marrow stem cells. T cell precursor cells arrive in thymus and spend up to 7-21 days undergoing differentiation and proliferation into a mature, but antigen naive, phenotype.

Question 2

Where do most T cells die?

Answer 2

• About 5 x 107 cells are made in thymus every day
• Only 2-4% of these cells leave thymus as mature T cells to populate lymph nodes etc. What happens to the rest? Thymus maintains same size.
• Over 95% of thymocytes die in thymus. What is going on?

Question 3

Describe the process of educating T cells

Answer 3

• Small double positive thymocytes (CD4 and CD8) initially express low levels of the receptor they use to recognise antigen, the TcR.
• Most of these TcRs won’t recognise your own Major Histocompatibility Complex (MHC) molecules (more on them later), so the T cells die because of a lack of ‘positive selection’.
• Those cells that do see your own MHC go on to mature and express high levels of TcR. They then lose either CD4 or CD8 to become single positive cells.
• During this latter stage the T cells also undergo ‘negative selection’, to eliminate T cells that see your own MHC with high affinity, ie which could become autoreactive T cells.

Question 4

What does thymic education result in?

Answer 4

he release into the periphery

of cells that are ‘restricted’ to recognising your own MHC.

Question 5

What is the MHC?

Answer 5

Major Histocompatibility Complex

Question 6

Describe the structure of the T cell receptor

Answer 6

Almost like an immunoglobulin, but not quite

Made of alpha and beta polypeptide chains w variable and constant regions found extramembranously

Question 7

Describe the structure of the TcR binding site

Answer 7

Very similar to an antibody

TcR and antibodies are evolutionary related. Both are members of the ‘Immunoglobulin Superfamily’ .

Question 8

How are TcR genes varied?

Answer 8

TcR undergo chromosomal rearrangement, similar to antibody genes

Question 9

What is a basic summary of TcR - MHC interaction?

Answer 9

• Antibodies ‘see’, ie bind the antigen they were raised against on its own, that is, free in solution, or maybe in a membrane.
• But, the TcR only ever recognises an antigen when it is bound by an MHC molecule. In other words TcR recognition of antigen is ‘MHC- restricted’

Question 10

What type of molecules do MHC molecules bind?

Answer 10

peptides

Question 11

Why do MHC molecules bind peptides?

Answer 11

Protein antigen in cell is processed by breakdown of antigen protein can then be presented on the MHC externally

Question 12

What are the two types of MHC molecules?

Answer 12

MHC class I
MHC class II

Question 13

Describe MHC class I

Answer 13

• Two chains, a heavy chain, and a small !2- microglobulin
• Upper surface forms a groove into which small 8-10 amino acid peptides sit.
• Expressed on almost every cell in your body, though at low levels in some (eg CNS)

Question 14

Describe MHC class II

Answer 14

• Two chains, alpha and beta, both membrane bound
• Upper surface forms groove into which longer peptides, over 20 amino acids sits.
• Expression more limited to specialised antigen presenting cells and immune cells, eg macrophages, dendritic cells, B and T cells.

Question 15

What are the different MHC classes recognised by?

Answer 15

MHC class I is recognised by CD8 T cells, MHC class II is seen by CD4 T cells

Question 16

What is a summary of the two types of MHC?

Answer 16

• The two MHC types pickup peptides from very different environments.
• MHC class I picks up peptides mostly derived from the internal contents of your cells, eg cytoplasm and nucleus.
• MHC class I meets peptides in the endoplasmic reticulum (ER)
• MHC class II picks up peptides derived from external sources, ie outside your cells
• MHC class II molecules meet peptides in endosomes.

Question 17

How many forms may MHC molecules take?

Answer 17

An absolute ton, MHC molecules are highly polymorphic

Question 18

Where are the polymorphisms of MHC located?

Answer 18

In the peptide-binding groove

This means that each different MHC molecule will present different Peptides to the immune system.

Question 19

Why is it important to understand MHC molecules?

Answer 19

Autoimmunity: many MHC molecules are associated with autoimmune diseases
Transplantation: the major factor in graft rejection is MHC disparity
Cancer. A multitude of tumour lines from the different stages of B and T cell development.
Acute lymphoblastic leukemia
Thymoma
Acute lymphoblastic leukemia
Adult T cell leukemia, Chronic lymphocytic leukemia
Hodgkin’s disease
Superantigens - toxic shock syndrome
DiGeorge’s syndrome - failure to develop thymic epithelia, few T cells
Severe combined immunodeficiency (SCID)
Bare lymphocyte syndrome

Question 20

What is the impact of MHC molecules on transplantation?

Answer 20

The major factor in graft rejection is MHC disparity. Why? Your own T cells are educated to see your own MHC molecules. Anyone else’s are similar, but just different enough to cause a response. Thus MHC matching is crucial to improve graft survival. Even if a full match is obtained, you have enough different peptides (called minor transplantation antigens) to trigger a slow graft rejection, so immunosuppression still required.

Question 21

What are some autoimmune diseases associated with MHC molecules?

Answer 21

Ankylosing spondylitis and HLA-B27. Multiple sclerosis and HLA-DR2. Type I IDDM and HLA-DR3/DR4. Rheumatoid arthritis and HLA-DR4.