B+T cells + MHC

Question 1

1. define HLA
2. define MHC

Answer 1

1. human leukocyte antigen system: immune system involved in protecting the body from pathogens and foreign bodies
2. major histocompatibility complex: which binds antigens to the cell surface by the recognition of T cells

Question 2

T cells:

1. where are T cells derived from?
2. where are they soon after production? for how long and for what reason?
3. where is the thymus situated and what does it do?

Answer 2

1. T cells derive from bone marrow (haematopoietic stem cells) stem cells
2. unlike B cells which go straight to the secondary lymph organ, the 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
3. the thymus sits above the heart (in blue) and disappears over age - it is important in determining what T cells do

Question 3

what are the 5 steps to educating T cells?

Answer 3

1. Small double positive thymocytes from bone marrow (with two molecules on surface: CD4 and CD8) initially express low levels of the receptor they use to recognise antigen, the TcR.
2. T cell receptor is designed to interact with MHC: but at this stage, most of these TcRs won’t recognise your own Major Histocompatibility Complex (MHC) molecules, so the T cells die because of a lack of ‘positive selection’
3. The cells that do see your own MHC go on to mature and express high levels of TcR
4. They then lose either CD4 or CD8 to become single CD4/CD8 positive cells
5. 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

1. what is the structure of T cell receptors?
2. what is the difference between antibodies and T cells?

Answer 4

1. T cell receptors, are similar to antibody receptors, with 2 polypeptide chains, both membrane bound with a V domain (variable) and C domain (constant)
2. antibodies ‘see’, ie bind the antigen they were raised against on its own, that is free in solution or maybe in a membrane

but

TcR (T cells) only ever recognise antigens when they are bound by an MHC molecules, this makes the TcR recognition of antigens MHC-restricted

Question 5

MHC molecules:

1. what is the main function of MHC molecules?
2. how are the two classes of MHC molecules recognised differently?

Answer 5

1. the main function of MHC molecules is to bring antigen to the cell surface by the recognition of T cells
2. MHC class 1 - recognised by CD8 T cells
   MHC class 2 - recognised by CD4 T cells

Question 6

1. what is the structure of MHC class 1 molecules?
2. where are they expressed?
3. where do MHC class 1 molecules pick up peptides?
4. what are the steps to this meeting of peptides?

Answer 6

1. MHC class 1 molecules have two chains: a heavy chain and a small beta2 microglobulin chain and an upper surface forms a groove into which small 8-10 amino acid peptides sit
2. expressed on almost every cell in your body, though at low levels in some (e.g CNS) - which recognise pathogens
3. • 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 endoplasmic reticulum (ER)
4. 1. Cytoplasmic proteins/intracellular antigens within the cell which don’t last forever as they get damaged or fall apart, which get chopped up by a proteosome
5. These are passed to the endoplasmic reticulum
6. They become bound to class one molecules and come out on the cell surface for CD8 positive T cells to look at

Question 7

1. what is the structure of MHC class 2 molecules?
2. where are they expressed?
3. where do MHC class 2 molecules pick up peptides?
4. what are the steps to this meeting of peptides?

Answer 7

1. MHC class 2 molecules have two chains: alpha and beta, both membrane bound and an upper surface forms groove into which longer peptides, over 20 amino acids sit
2. expression more limited to specialised antigen presenting cells and immune cells e.g. macrophages, dendritic cells, B and T cells
3. • MHC class 2 picks up peptides derived from external sources, outside your cells and processed and taken into your cells. MHC class 2 molecules meet peptides in endosomes
4. 1. they are also made in the ER as ER proteins
5. before being pushed to the cell surface, they are pushed towards endosomal compartments in which they are then they meet pathogens which have been chopped up by lysosomes and endosome into small peptide fragments
6. they bound to these cluster molecules and come out on the cell surface for CD4 positive T cells

Question 8

MHC molecules are highly polymorphic, explain what this means and what it means clinically?

Answer 8

• MHC molecules are highly polymorphic meaning they occur in many different forms
• polymorphisms are located in the peptide-binding groove which means that each MHC molecule will present different peptides to the immune system
  • this is why organ transplantation isn’t always successful and the organ is rejected

Question 9

clinical importance:

many MHC molecules are associated with autoimmune diseases, list 4

Answer 9

1. Ankylosing spondylitis
2. Multiple sclerosis
3. Type I diabetes mellitus
4. Rheumatoid arthritis

Question 10

clinical importance:

explain how transplantation/graft rejection can be caused by MHC molecules and T cells

Answer 10

• your own T cells are educated to see your own MHC molecules, 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

(Immunosuppression isa reduction of the activation or efficacy of the immune system)

Question 11

clinical importance:

explain the effect of superantigens?

Answer 11

superantigens: some bacteria and viruses produce proteins that interfere with the interaction of TcR and MHC, stimulating large number of T cells - for example staphylococcal enterotoxin (SEB) and Toxic shock syndrome