T and B cells : MHC Flashcards
Where are T cells derived from ?
T cells derive from bone marrow stem cells.
Where do T cells mature ?
T cell precursor cells arrive in the thymus and spend 7-21 days undergoing differentiation and proliferation into a mature, antigen naive, phenotype.
Describe the fates of T cells in the thymus
2-4% of thymocytes leave the thymus as mature T cells to populate the lymph nodes.
Over 95% of thymocytes die in the thymus.
State some examples of thymocytes
CD4
CD8
Describe educating T cells
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.
HLA
Human Leukocyte Antigens
- found in humans only
MHC
Major Histocompatibility Complex
- umbrella term
Function of negative selection
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)
Function of educating T cells
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.
Describe T cells which have been educated
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.
What does thymic education result in ?
Results in the release into the periphery of cells that are restricted to recognising your own MHC.
Describe the T cell receptor
Shares sequence similarities with immunoglobulins, but it is a bit different.
2 polypeptide chains, membrane bound, each with a V and C domain.
What is the T cell receptor binding site similar to ?
TcR binding site is very similar to an antibody.
Both are members of the Immunoglobulin superfamily.
How do you generate diversity in TcR’s ?
TcR undergo chromosomal rearrangement, similar to antibody genes.
Key feature of TcR
Only ever recognises an antigen when it is bound by an MHC molecule.
- TcR antigen recognition is MHC restricted
Function of MHC molecules
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)
Where is HLA found ?
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.
State the 2 types of MHC molecules
MHC class 1
MHC class 2
Where is MHC class 1 expressed ?
Expressed on almost every cell in your body, though at low levels in some (e.g. CNS)
Describe structure of MHC class 1
2 chains
- Heavy chain
- Small Beta2-microglobulin
Upper surface forms a groove in which small 9-11 amino acid peptides sit.
Where is MHC class 2 expressed ?
Expression more limited to specialised antigen presenting cells and immune cells.
e.g. Macrophages, dendritic cells, B and T cells
Describe the structure of MHC class 2
2 chains
- Alpha and Beta, both membrane bound
Upper surface forms a groove into which longer peptides, over 20 amino acids sits.
Describe MHC molecule recognition
The 2 MHC molecule types are seen by different T cells.
MHC class 1 - CD8 T cells
MHC class 2 - CD4 T cells
What is the difference between a CD4 T cell and a CD8 T cell ?
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)
MHC class 1 VS MHC class 2
Class 1: shorter peptide groove
Class 2: longer peptide groove, groove is more shallow
Where do MHC class 1 molecules pick up and meet peptides from ?
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
Where do MHC class 2 molecules pick up and meet peptides from ?
MHC class 2 - picks up peptides derived from external sources (i.e. outside your cells)
MHC class 2 molecules meet peptides in endosomes.
State some differences between the MHC classes
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.
CD8 T cells
Cytotoxic T cells
CD4 T cells
Helper T cells
Function of interaction with MHC class 2
Interaction of T cells with MHC class 2 drives the secretion of cytokines to help boost other immune responses.
Function of interaction with MHC class 1
Interaction generates killer T cells
Describe MHC class 1 meeting peptides
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.
Describe MHC class 2 meeting peptides
Peptide production in phago-lysosome
Peptide binding by MHC class 2
MHC class 2 presents peptide at cell surface.
Feature of HLA class 1 and 2 molecules
They are incredibly diverse
- MHC molecules are highly polymorphic
Where are polymorphisms located ?
Located in the peptide-binding groove
Each different MHC molecule will present different peptides to the immune system.
State some examples of diseases with an HLA association.
Autoimmunity
- Ankylosing spondylitis
(association with class 2 MHC)
- Multiple sclerosis
- Diabetes
- Rheumatoid arthritis
What is a major factor in graft rejection in transplantation ?
MHC disparity
T cells are educated to see your own MHC molecules, anyone else’s are similar but different enough to cause a response.
What can improve graft survival rates ?
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.
Cancer
A multitude of tumour lines from the different stages of B and T cell development.
Hodgkins disease
B cell lineage
Large cells
Superantigens
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
DiGeorges syndrome
Failure to develop thymus epithelia, few T cells are produced.
Severe combined immunodeficiency
Loss of the T cell compartment leads to loss of ability to produce cell mediated and antibody response.
Bare lymphocyte syndrome
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.
