Introduction to the Immune System 5 Flashcards
What are T cells derived from?
derive from common lymphoid progenitor (in bone marrow) but migrate to the thymus for majority of their development.
Once matured what do T cells do?
They enter the bloodstream and migrate to secondary lymphoid organs
Where does the majority of the maturation of T cells occur?
In the thymus
What do immature T cells acquire in the thymus?
There own specific antigen receptor which will be unique to that T cell
Where do mature naive T cells travel?
They keep recirculating from lymphoid to lymphoid anti, they encounter their complimentary receptor
What happens when a naive T cell encounters is complimentary antigen?
The T cell becomes activated and undergoes the final stage of differentiation to become an effector T cell
These cells proliferate and differentiate into effector cells
What is the function of a T cell?
To recognise and bind to antigens
How to T cells bind and recognise antigens?
Via a specific antigen receptor
What is the T cell receptor made up of?
Consist of 2 polypeptide chains, α and β, linked by a disulphide bond.
Similar to a single Fab fragment of antibody, has one antigen binding site.
Which family do T cell receptors being to?
members of the immunoglobulin superfamily
T cells can only recognise antigens when…
it is complexed in an MHC not just on its own
Other than T cell receptors what the molecules do all T cells present?
CD3
What does CD3 complex with?
Our T cell receptors to send signals into the cells
Does CD3 actually bind to antigens?
NO it only recognises when an antigen is bound to the T cell
Which molecule is specific to cytotoxic T cells?
CD8
What is the main function of cytotoxic T cells?
Kill virus infected cells or malignant cells
Which molecule is specific to T helper cells?
CD4
What is the main function of T helper cells?
They increase macrophage function
They provide help to the B cells for antibody production
How are T cell receptors generated?
In a similar process to B cells
Uses recombinant activates gene (RAG) proteins to perform V(D)J somatic recombination.
Guided by 12/23 RSS rule.
Describe the structure of T cell receptors
2 polypeptide chains, α and β, linked by a disulphide bond A transmembrane region Amino acid binding site Antigen binding site Cytoplasmic tails
What does each polypeptide chain in a T cell receptor have?
A variabel region
A constant region
What does the transmembrane region do in a T cell receptor?
Polypeptides are inserted into this region so that they are inserted in to the plasma membrane pf the T cell so that they are expressed on the outside of the T cell
Where is the amino acid binding site found on the T cell receptor?
At the amino terminus end of each polypeptide chain
What makes up the antigen binding site?
Both the polypeptide chains
What does MHC stand for?
Major histocompatibility complex
What do MHCs do?
They bind and present antigens to T cells for inspection via TCR.
What are MHCs made up of?
Transmembrane glycoproteins that are highly polymorphic
What does polymorphism in MHC lead to?
Can lead to transplant graft injection
This is why we need to do a tissue type matching
What type of antigen is presented on an MHC?
Both intra cellular and extracellular antigens are processed and presented at the cell membrane for inspection within MHC
How many CLASS of MHC do we have?
2: MHC class I MHC class II
What does MHC I do?
binds and presents intracellular derived antigen (eg malignant cells)
Which of the types of MHC is carried out by the majority of nucleated cells?
MHC I
Which cell is MHC I not present in?
Red blood cells
Is the process carried out by MHC I specific?
NO all types of proteins are presented by the MHC I molecules
It will present everything both self and non self proteins
Why is it important that all cells can perform MHC I presentation?
As all of our cells can be infected by viruses
Where are viral proteins made?
Within a cell but the stuff they produce is no self
So the antigen is intracellular
Other than viruses what other reason can cells be presenting a non self intracellular antigen?
Mutated tumour antigens
What does MHC class II do?
binds and presents extracellular derived antigen.
Which cells can carry out MHC II presentation?
ONLY Carried out by professional Antigen presenting cells (APC).
What do MHC II bind to?
Binds to bacteria or their products that have then been ingested and presents these antigens
What are the differences in the structure of MHC class I and MHC class II
MHC class I is made up of a one long alpha chain and a smaller beta chain Only the alpha chain contributes to the antigen biding groove
MHC II is made up of one alpha and beta chain both similar sizes
Both alpha and beta contribute to the antigen binding groove
What are the similarities in the structure of MHC class I and MHC class II
Both have a peptide binding groove
Both are composed of 2 polypeptide chains
On which cells are MHC class I proteins present
All somatic cells
On which cells are MHC class II proteins present
Dendritic cells
B cells
Macrophages
For MHC I what sized residues will fit into the antigen binding site?
8-10 residues
For MHC II what sized residues will fit into the antigen binding site?
13 residues.
What is protein turnover?
old proteins being replaced by new ones
The constant degradation of proteins in our cells
When a cell has been infected what will that infected cell be doing>
above will be degrading both its own and the viral proteins indiscriminately down to small peptides of about 10 amino acids in length.
What happens to the small peptides our infected cells make?
They are transported into the endoplasmic reticulum through a specialised transporter channel called TAP
What does the transporter channel called TAP do?
It transports small peptides in infected cells into the endoplasmic reticulum
What does TAP stand for?
Transporter associated with antigen processing
What else is happening as small peptides are being moved into the endoplasmic reticulum in infected cells?
Class I MHC is meanwhile being synthesised on the ribosomes of the rough endoplasmic reticulum into the lumen
The large and small chains of Class I MHC come together and a functional MHC I is formed
What does the binding groove of the Class I MHC bind to in an infected cell?
Binds to the incoming small peptides
Both the cells own proteins and the virus’ proteins
What happens to the MHC class 1 molecule after it has been loaded with proteins in the RER?
The usual cell transport mechanisms takes place, with the endoplasmic reticulum feeding into the Golgi apparatus
Eventually the Class I MHC is inserted through the cell membrane
There it presents its peptide (antigen) for inspection by circulating T cells
What is class I MHC recognised by?
Recognised by the specific T-cell receptor of Cytotoxic T-lymphocytes (CTLs)
What will happen if the Class I MHC Is presenting a foreign antigen?
If the Cytotoxic T-lymphocytes has a complimentary T cell receptor the infected cell will be triggered and killed
What type of antigen do class I MHC present?
Intracellular antigens
What does the recognition and killing of infected cells (due to MHC class I presentation) ensure?
Ensures that the infected cell presenting the antigen is eliminated, restricting the infection
What will happen id the Class I MHC Is presenting a self protein?
The Cytotoxic T-lymphocytes ignores it and moves on without activation
Class II antigen processing is done by which cells?
Only carried out by specialised cells of the immune system, dendritic cells, Macrophages and B cells
Why is the processing of class II antigens more complicated?
Because it is only done by specialised cells which themselves are still carrying to class I processing
What mechanism does class II antigen processing provide fro the immune system?
Provides a mechanism by which the immune system can deal with invading pathogens which are outside the cells themselves eg bacterial infection
Once a macrophage has engulfed a foreign pathogen what happens?
It degrades the pathogen down into small peptides around 10 amino acids in length
While the pathogen is being degraded what are the class II MHC doing in the macrophages?
They are being synthesis in the usual way in the rough endoplasmic reticulum and are assembled into functional molecules
How do we stop MHC class II from binding to intracellular antigens in the macrophage?
a small peptide, called the invariant chain is produced to stop MHC class II from binding to intracellular antigens
What does the invariant chain have a strong affinity to and what does this mean?
Has a very high affinity for Class II MHC and outcompetes all incoming intracellular peptides, which therefore do not bind to Class II MHC because the antigen binding pocket has been filled by the invariant chain
Where does the Class II MHC with the invariant chain positioned within it antigen binding groove than go?
Then passes through the Golgi, fusing with a further endosome containing enzymes.
What do the enzymes endosomes do to the Class II MHC with the invariant chain positioned within it antigen binding groove?
These enzymes degrade the invariant chain down to a small residue, called CLIP, which no longer has the same affinity for the antigen binding pocket
What happens to the vesicles containing the extracellular peptides and the vesicle containing Class II MHC containing CLIP?
They fuse together and are joined by a third vesicle which contains a further protein produced in the rough endoplasmic reticulum, DM
Describe the structure of DM
DM is structurally similar to Class II MHC but it differs from Class II MHC in having an extremely high binding affinity for CLIP
Which 3 vesicles fuse in the macrophage during class II antigen processing?
- Vesicle containing Class II MHC containing CLIP
- Vesicle containing the
extracellular peptides - Vesicle with DM
What happens after the fusion of three vesicles in the macrophage during class II antigen processing?
DM outcompetes Class II MHC for CLIP and the antigen binding pocket of Class II MHC can now bind to extracellular antigen
After CLIP detaches from the class II MHC what happens?
The MHC II is inserted through the macrophage membrane displaying its captured antigen for inspection by passing T cells
Which cells recognise Class II MHC?
Helper cells
What happens if the antigen contained within the Class II MHC is recognised by the Helper cell as foreign?
the Helper cell is activated and produces protein messenger molecules (called lymphokines) which stimulate immunoglobulin production by B-cells as well as stimulating other cells of the immune response
What happens if the antigen contained within the Class II MHC is NOT recognised by the Helper cell as foreign?
the Helper cell ignores it
Which CD pairs with MHC I?
CD8
Which CD pairs with MHC II?
CD4
The T cell receptor of CD8 cytotoxic t cell binds to what?
MHC class I peptide complex
The T cell receptor of CD4 t helper cell binds to what?
MHC class II peptide complex
Why do our naive T cells need to be primed?
To be able to produce a clonal army and produce memory cells
What initiated the priming of naïve T cells?
Requires presentation of antigen of correct specificity by antigen presenting cell to naïve T cells
Describe the process of priming naïve t cells
- Antigen is picked up in tissues by dendritic cell and taken to lymph node.
- Recirculating T cells leave the blood vessel and enter the lymph node.
3, They encounter the dendritic cells presenting the antigen - If they encounter a specific antigen they proliferate and differentiate into effector T cells.
Name the 3 different types of antigen presenting cells
- Dendritic cells
- Macrohages
- B cells
What can dendritic cells do?
can take up antigen from all sources
What is the main function of dendritic cells?
main function to prime naïve T cells, drive initial T cell clonal expansion.
What are macrophages specialised in doing?
specialise in processing antigen from intracellular pathogens.
Present to effector T cells.
What do B cells do?
They present to effector T cells
What are B cells specialised in?
specialise in processing antigen from intracellular pathogens.
Present to effector T cells.
Where are all the professional antigen presenting cells found?
In the lymphnodes
What do t cell receptors recognise?
They recognise MHC proteins and peptide complexes
Name the 4 types of effector T cells
CD8 cytotoxic T cells
CD4 helper T cells 1
CD4 helper T cells 2
CD4 regulatory T cells
What do cytotoxic T cells do?
They kill virus infected cells
What do CD4 helper T cells 1 do
They activate infected macrophages
They also provide help to B cells for antibody production
What do CD4 helper T cells 2 do ?
They provide help to B cells for antibody production They especially help in class switching to IgE
What do CD4 regulatory T cells do?
Suppress t responses
How do cytotoxic T cells kill cells?
- They Patrol tissues for any cells bearing it’s specific antigen presented in MHC I.
- Recognises antigen + MHC I on cell surface
- It Forms an Immunological synapse, polarises cytotoxic granules towards the target cell.
- Granule membranes fuse with the plasma membrane of the CTL, toxic contents released in direction of target.
5, Perforin generates a pore within target cell membrane, Granzyme B + others enters cell inducing apoptosis - Cell dies and cytootcix T cells moves on to next target
What do helper T cells release>?
Different lymphokines
Where are t follicular helper cells found?
In the follicles of the lymph nodes
What does t helper cell 1 do?
Increase macrophage activity against intracellular bacteria
What does t helper cell 2 do?
Promote responses to parasites, helping B cells class switch to IgE.
What donut t follicular helper cells do?
Provides B cell help for production of high affinity antibody.
What is the effect of t helper cell activation?
Essential activation, coordination and control of immune responses.
What happens when helper T cells are infected?
Can cause immune collapse
Name a disease that affects helper t cells
HIV
What is self tolerance ?
The state of not responding to our own cells and molecules is called self tolerance
How do we maintain self tolerance?
Through the process of clinical deletion
How are T cells selected?
T cells are selected through positive and negative selection processes in the thymus
Describe the selection process of helper t cels
- Thymocytes produced in the bone marrow do not express T cell receptors, CD4 or CD8
- These thymocytes relocate to the thymus
- Theres rearrangement of T cell receptor gene segments
- Expression of T cell receptors, CD4 and CD8 on the immature T cells
- Positive and negative screening processes occur
- Survivors mart to become mature cytotoxic t ells and t helper ells
What are Thymocytes?
Immature T cells
What are positively selected cells?
They are t cells that can recognise MHC I and II
What happens if a t cell cannot recognise MHC?
Leads to apoptosis and cell death
Where does positive and negative selection of Thymocytes occur?
in the thymus
Which T cells are negatively selected ?
Cells that can bind to MHC and self peptides are negatively selected
What happens to cells that are negatively selected?
They undergo apoptosis and die
After undergoing positive and negative selection which cells are left?
Cells that can interact with MHC BUT do not react strongly with a self peptide survive
What percentage of precursor T cells are screened out before they mature?
98%
